Skip to main content

The role of KLRG1: a novel biomarker and new therapeutic target


Killer cell lectin-like receptor G1 (KLRG1) is an immune checkpoint receptor expressed predominantly in NK and T-cell subsets that downregulates the activation and proliferation of immune cells and participates in cell-mediated immune responses. Accumulating evidence has demonstrated the importance of KLRG1 as a noteworthy disease marker and therapeutic target that can influence disease onset, progression, and prognosis. Blocking KLRG1 has been shown to effectively mitigate the effects of downregulation in various mouse tumor models, including solid tumors and hematologic malignancies. However, KLRG1 inhibitors have not yet been approved for human use, and the understanding of KLRG1 expression and its mechanism of action in various diseases remains incomplete. In this review, we explore alterations in the distribution, structure, and signaling pathways of KLRG1 in immune cells and summarize its expression patterns and roles in the development and progression of autoimmune diseases, infectious diseases, and cancers. Additionally, we discuss the potential applications of KLRG1 as a tool for tumor immunotherapy.


KLRG1 is an inhibitory lectin-like type II transmembrane glycoprotein receptor characterized by an extracellular c-type lectin structural domain, a transmembrane structural domain, and an inhibitory motif for the cytoplasmic immunoreceptor tyrosine-based inhibitory motif (ITIM) [1]. To date, this receptor has been described in diverse subsets of lymphocytes, including natural killer (NK) cells, as well as distinct subsets of T-cells, such as CD8+ T-cells, CD4+ T-cells, and regulatory T-cells (Tregs) [2,3,4,5]. The extracellular domain of KLRG1 on immune cells can be assessed via immunofluorescence staining and flow cytometry using KLRG1-specific antibodies, enabling the quantification of its expression level [6, 7]. As a ligand of KLRG1, cadherin is widely expressed on antigen-presenting cells (APCs) and tumor cells and binds to the extracellular domain to achieve signal transduction [8, 9]. Signaling through the binding of KLRG1 to cadherin occurs only secondarily to the successful activation of lymphocytes via the T-cell receptor (TCR) with its cognate major histocompatibility complex or other activating receptor ligand, followed by the phosphorylation of downstream proteins, including AKT or AMP-responsive protein kinase (AMPK) [10,11,12]. The primary function of KLRG1 is to provide stimulatory (costimulatory) and inhibitory (coinhibitory) signals, thereby regulating the activation and proliferation of immune cells to self-antigens and foreign antigens and participating in cell-mediated immune responses [13]. The most characteristic inhibitory functions attributed to KLRG1 include the induction of immune cell death or exhaustion through autophagy, the suppression of cytotoxicity, and the inhibition of cytokine production [9, 14].

Recent advances have shown the crucial role of KLRG1 in the pathogenesis and progression of autoimmune disorders, infectious diseases, and malignancies, underscoring its potential utility as a promising immune cell marker for disease prediction, diagnosis, and prognostication [15, 16]. Nevertheless, the expression levels of KLRG1 and the signal transduction pathways in which it is involved exhibit variation among distinct immune cell types [5, 10,11,12, 17], suggesting diverse regulatory mechanisms and clinical implications in different disease states. In the context of human physiology, KLRG1 has been subjected to thorough investigation across a spectrum of disease states, spanning expedited immune responses to malignant tumor progression. These states include infections, autoimmune disorders, solid tumors, and hematological malignancies (HMs) [16, 18,19,20,21]. Ideally, the inhibitory effect of anti-KLRG1 antibody for KLRG1 on immune cells can effectively enhance adaptive immune function or improve vaccine efficacy [11, 22]. Thus, the development of KLRG1-targeted inhibitors, which have emerged as a prominent area in the field of immunotherapy, has accelerated [8, 23,24,25]. Anti-KLRG1 monoclonal antibodies (mAbs) significantly increase the antitumor activity of immune cells and reduce the worsening of disease in cancer mouse models [8, 24, 26]. Importantly, an anti-KLRG1 mAb (ABC008) for treating autoimmune diseases and hematologic malignancies is already in development [27] and is a novel, promising strategy for disease treatment [8, 24]. Upon the approval of anti-KLRG1 mAbs for therapeutic use, the assessment of KLRG1 levels is poised to assume a critical role as a biomarker in clinical evaluation [16, 28]. Nevertheless, the existing evidence falls short of conclusively addressing specific concerns. First, while KLRG1 expression has been detected in various cell types, including tumor cells, a systematic and comprehensive summary of the potential mechanisms underlying its role is lacking. Second, the differences in the expression and role of KLRG1 in various diseases and the feasibility and clinical significance of KLRG1 as a disease marker have not been summarized. Finally, recent clinical studies of KLRG1 inhibitors have focused only on inclusion body myositis (IBM) and T-cell large granular lymphocytic leukemia diseases, and the feasibility of using KLRG1 as a potential therapeutic target for other diseases still needs to be studied.

Hence, we present a comprehensive review elucidating the distribution, structural attributes, and functional signaling pathways of KLRG1 across various cell types, delineating its multifaceted involvement in assessment of the progression of disease pathogenesis. These findings demonstrate its significance as a biomarker in autoimmune and infectious diseases, as well as its contribution to immune modulation within both solid and hematological tumors. Additionally, we offer an overview of the recent advancements in KLRG1 inhibitor development for tumor immunotherapy, underscored by the promising synergistic efficacy of KLRG1 inhibitors combined with other targeted inhibitors.

Regulation of immune signaling by KLRG1

Differences in KLRG1 between mice and humans

KLRG1, known as a mast cell function-associated antigen, was initially characterized in RBL-2H3 mast cells from rats in 1991 [29]. In contrast to that in rats, KLRG1 is not expressed on mast cells in mice or humans [2, 13, 30]. Recent advances indicate that KLRG1 is expressed on immune cells, mainly NK cells, CD8+ T lymphocytes, CD4+ T lymphocytes, and other T cell subsets of γδ T-cells, follicular helper T-cells, follicular regulatory T-cells and regulatory T-cells in mice and humans [2,3,4,5, 17, 31, 32]. In addition, KLRG1 is expressed mainly on mature cells and is expressed at relatively low levels or not expressed on naïve cells, while KLRG1 is heterogeneously expressed on memory T-cells and NK cells [33].

The location and length of the KLRG1 gene and the structure of the KLRG1 protein differ between mice and humans (Table 1). First, the KLRG1 gene is located on chromosome 6 in mice and chromosome 12 in humans and is transcribed into mRNA by a promoter, followed by selective splicing of KLRG1 mRNAs into different forms, and only stable KLRG1 mRNAs are translated into KLRG1 proteins [34,35,36]. The extracellular c-type lectin structural domain of the KLRG1 protein is expressed on the cell membrane and undergoes modification processes such as glycosylation and phosphorylation to exert its effects [37]. The mouse KLRG1 gene (mKLRG1) is approximately 13 kb in total length and is composed of five exons and four introns [34]. The length of the rat KLRG1 (rKLRG1) gene is approximately 13 kb, while that of the human KLRG1 (hKLRG1) gene is approximately 19 kb. The rKLRG1 and hKLRG1 homologs share 89% and 71% similarity with the mouse gene, respectively, with each featuring five exons and four introns [3, 30, 34]. Regarding the KLRG1 protein, there are specific variations in structure between mice and humans, with 57% identity at the amino acid level [38]. Biochemical analyses have indicated that, compared with programmed cell death protein 1 (PD-1), which is expressed mainly as a monomer on the surfaces of cell membranes, mKLRG1 can form monomers, dimers, trimers, and tetramers that are connected by disulfide bonds. In contrast, hKLRG1 exists only as a disulfide-linked dimer [6]. Unlike for PD-1, no study has yet described soluble KLRG1, which may be due to KLRG1 existing mainly as a homodimer. In addition, Hofmann et al. compared the inhibitory capacities of different polymerized forms of KLRG1 by altering the mKLRG1 protein and reported that only disulfide-linked dimeric KLRG1 had a significant inhibitory capacity [39], possibly resulting in a lower inhibitory capacity of mKLRG1 than of hKLRG1. Although there are differences between mKLRG1 and hKLRG1, their binding abilities to cadherin are similar [40]. Therefore, KLRG1-related studies based on mouse models may have some reference value for human disease research, but whether KLRG1 can serve as a biomarker for evaluating disease development or as a therapeutic target still needs to be determined by further clinical study.

Table 1 Differences in KLRG1 between mice and humans

Signaling pathways of KLRG1

The regulatory pathways of KLRG1 in immune cells have undergone extensive investigation, revealing both commonalities and distinctions in the regulatory pathways and functions of KLRG1 across diverse cell types. Functionally, KLRG1 can act as an immune checkpoint receptor to regulate immune cell proliferation and the immune response by binding to its ligand cadherin via the phosphoinositide 3-kinase (PI3K)/AKT pathway or the AMPK pathway [10, 30, 41,42,43]. Rosshart et al. reported that spatially linked co-engagement of KLRG1 and TCR/CD3 is a prerequisite for KLRG1 function [43]. When cadherin binds to the extracellular domain of KLRG1, ITIM tyrosine is phosphorylated, thereby inhibiting lymphocyte function [44]. mKLRG1 can recognize and bind to three prototypical cadherins, namely, E-cadherin (E-cad), N-cadherin (N-cad), and R-cadherin (R-cad) [9, 45]. The interaction of KLRG1 with E-cad, N-cad, or R-cad increases the activation threshold of NK and T-cells, thereby inhibiting the cytotoxicity of NK cells to prevent damage to tissues expressing these cadherins [9, 46,47,48]. This mechanism represents a protective measure of the body against excessive immune activity. KLRG1 binds to the N-terminus of the monomeric form of E-cad [46], and this interaction between KLRG1 and E-cad inhibits the proliferation and cytokine production of type 2 innate lymphoid cells (ILC-2s) [49]. The E-cad/KLRG1 pathway plays a significant role in inhibiting the antitumor activities of T-cells and NK cells (Fig. 1) [10, 24, 50]. KLRG1 mainly interacts with cadherin ligands expressed on the surfaces of cancer cells or APCs, subsequently recruiting tyrosine-protein phosphatases (Src homology 2-containing inositol phosphatase-1 (SHIP-1) and Src homology-2-containing protein tyrosine phosphatase 2 (SHP2)) following the phosphorylation of ITIM tyrosine residues within its cytoplasmic structural domain [44, 51]. The effectors SHIP-1 and SHP-2 regulate PI3K function by degrading phosphatidylinositol (3,4,5) trisphosphate (PIP3) to phosphatidylinositol (4,5) bisphosphate (PIP2) [51]. PI3K, consisting of the regulatory subunit p85 and the catalytic subunit p110, phosphorylates PIP2 to produce PIP3, which aids in phosphorylating AKT, thus regulating a series of downstream cellular responses, including survival, growth, proliferation, and migration [44, 52,53,54]. KLRG1 inhibits AKT phosphorylation by inhibiting the PI3K/AKT pathway, thereby attenuating the activation of the mammalian target of rapamycin (mTOR) signaling pathway, resulting in NK and T-cell proliferation dysfunction and reduced effector function [42, 50, 55, 56]. Furthermore, in hepatitis C virus (HCV)-driven CD4+ T-cells, KLRG1 can inhibit T-cell cycle progression through the p16ink4a/p27kip1 pathway [11]. During HCV infection, the increased expression of KLRG1 inhibits TCR-induced PI3K/AKT phosphorylation, which activates the forkhead box O (FOXO) transcription factor and increases expression of the cell cycle inhibitor p27kip1, resulting in growth arrest in the G1 phase by repressing the activation of cyclin E and cyclin-dependent kinase-2 (CDK2) [57, 58]. High KLRG1 expression resulting from HCV infection also increases the expression of p16ink4a in CD4+ T-cells, which blocks the activation of cyclin D and CDK4/6, leading to growth arrest in the G1 phase [59]. Suppression of the KLRG1 pathway and its downstream signaling molecules in CD4+ T-cells restores CD4+ T-cell cytotoxicity, providing a novel avenue for enhancing vaccine responses [5].

In highly differentiated human primary NK cells, KLRG1 can also inhibit the function of NK cells through the activation of AMPK, in addition to the classic PI3K/AKT pathway [10, 50]. KLRG1 is internalized after the E-cad/KLRG1 complex is formed and directly binds to AMPK to disrupt AMPK-protein phosphatase 2 C (PP2C) interactions. Subsequently, it inhibits the phosphatase activity of PP2C, preventing the dephosphorylation of AMPK by phosphorylated PP2C. This process enhances AMPK signal transduction rather than inducing de novo kinase activation [60]. Importantly, inhibiting KLRG1/AMPK signaling can prevent AMPK activation and reinstate NK cell cytotoxicity, cytokine secretion, proliferation, and telomerase expression, thereby bolstering immunity in aging individuals and in individuals with malignant tumors [10, 42]. Although human T-cells also express KLRG1 and have the AMPK signaling pathway [61], it is unclear whether KLRG1 plays a similar role in T-cells. In addition, KLRG1 can bind to membrane-bound N-cad, recruiting SHIP-1 and SHP-2, inhibiting NK cell and T-cell function, and inducing cardiac endothelial cell proliferation and angiogenesis [62, 63]. Moreover, KLRG1 can also cause functional depletion of NK cells by binding to soluble N-cad released by circulating tumor cells in a noncontact cell‒cell manner [48, 64]. R-cad binding to KLRG1 plays a similar role [9].

Fig. 1
figure 1

KLRG1 signaling pathway. KLRG1 expressed on the surfaces of T-cells interacts with cadherin ligands expressed on the surfaces of cancer cells or APCs, promoting the phosphorylation of the ITIM intracellular structural domain, followed by the recruitment of the tyrosine-protein phosphatases SHIP-1 and SHP-2. In contrast to PI3K, SHIP-1 and SHP-2 inhibit AKT phosphorylation by degrading PIP3 to PIP2, thereby attenuating the activation of the mTOR pathway, leading to reduced T-cell effector function and proliferative dysfunction. In HCV-infected CD4+ T-cells, an increase in KLRG1 expression can inhibit AKT phosphorylation, thereby activating the transcription factor FOXO and increasing expression of the cell cycle inhibitor p27kip1 or directly activating p16ink4a to inhibit T-cell cycle progression. In NK cells, in addition to affecting the AKT pathway, KLRG1 can also be internalized after binding cadherin ligands, after which it binds directly to AMPK and prevents AMPK dephosphorylation by the protein phosphatase PP2C, which amplifies the activity of AMPK and leads to loss of NK cell function. The figure was created at

Effect of KLRG1 on immune cells

Typically, 30% of resting NK cells in mice express KLRG1 [14], while in humans, 60% of healthy adult NK cells express KLRG1 [30]. KLRG1 is a marker of T-cell senescence [65]. KLRG1 is highly expressed in T-cells from senescent patients, and its expression increases with age [42, 65, 66]. In addition, the proportion of highly differentiated T-cells increases in older individuals, and the expression of KLRG1 is correlated with the degree of cellular differentiation [67]. KLRG1 expression increases with the degree of cellular differentiation in NK cells and T-cells and is overexpressed in mature cells, with the highest expression in memory cells and highly differentiated end-stage cells, suggesting that KLRG1 can be used as a marker of lymphocyte differentiation [7]. KLRG1 can also serve as an indicator to distinguish short-lived effector cells from memory precursor effector cells. During acute viral infection in mice, KLRG1 is a marker for short-lived effector CD8+ T-cells [68, 69]. KLRG1-positive NK and T-cells have lower proliferative capacities than KLRG1-negative cells [7, 30, 65].

KLRG1 is not only a marker of T-cell senescence [70]. KLRG1 has an inhibitory cytoplasmic ITIM motif and thus may play an inhibitory role in the immune system [2, 14, 44]. KLRG1 can inhibit the proliferative capacity and effector function of NK cells and T-cells by inhibiting AKT phosphorylation or enhancing AMPK phosphorylation [9, 42]. After viral infection, the ability of mouse NK cells to produce interferon-γ (IFN-γ) is negatively correlated with KLRG1 expression [14].

The functionality of KLRG1 is modulated in a complex manner by factors such as its expression level, activation state, inflammatory factors, and other costimulatory molecules. The inhibitory potential of KLRG1 directly correlates with its expression on cell surfaces [39]. KLRG1 expression is positively correlated with age [10] but negatively correlated with the ability of NK cells to produce the proinflammatory factor IFN-γ [7, 14]. Furthermore, interleukin-2 (IL-2) can induce the expression of KLRG1 on tissue-resident Treg cells, but the specific regulatory mechanisms involved are still unclear [71].

In addition, the expression level of KLRG1 significantly increased after virus infection in mice [3, 14]. Interestingly, the costimulatory molecules PD-1 and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) may have potential regulatory mechanisms involving KLRG1 that influence the quantity and activity of target cells. For example, Taylor et al. reported that PD-1 signaling deficiency enhances signal transducer and activator of transcription (STAT)-5 activation, which increases the proliferation of KLRG1+ ILC-2 cells. Moreover, PD-1 antibody blockade also enhanced KLRG1+ ILC-2 cell quantity and antiparasitic helminth immune function [72]. CTLA-4, which binds to its ligand CD80, triggers the Hippo pathway, leading to Yes-associated protein degradation and consequently upregulating B lymphocyte-induced maturation protein 1 (Blimp-1) to promote terminal T-cell differentiation [73]. Blimp-1 is a transcription factor required for the differentiation of effector CD8+ T cells, and in the absence of Blimp-1, T cells fail to differentiate into KLRG1hi IL-7Rlow short-lived effector CD8+ T cells, resulting in reduced KLRG1 expression [74]. More research is needed to fully understand the relationship between KLRG1 and those costimulatory molecules. Moreover, the inhibitory effect of KLRG1 was negatively correlated with the expression level of the transferrin receptor on cell surfaces and decreased with increasing lymphocyte proliferation [75].

The role of KLRG1 in diseases

KLRG1 in autoimmunity

Autoimmune diseases are a group of diseases in which the body develops an abnormal immune response to self-antigens, resulting in self-tissue damage [76]. As an immune checkpoint receptor, KLRG1 may play a role in autoimmune diseases by regulating the effector functions and proliferative capacities of T- and NK cells and controlling immune tolerance [77, 78]. Numerous studies have shown that KLRG1 expression is increased on NK and T-cell subsets in patients with a variety of autoimmune diseases, including primary biliary cholangitis (PBC), IBM, systemic lupus erythematosus (SLE), and experimental autoimmune encephalomyelitis (EAE) [18, 56, 79,80,81] but is reduced in NK cells in the peripheral blood of patients with SLE [15] and is lacking in the peripheral blood of patients with autoimmune lymphoproliferative syndrome (ALPS) [56]. In summary, increased KLRG1 expression mostly positively correlates with disease severity [15, 18, 80, 81] or increases with the degree of T-cell differentiation and is positively correlated with cytotoxicity (Table 2) [79, 82, 83]. For example, KLRG1+ T-cell infiltration in liver samples from PBC patients is positively correlated with severe histologic hepatic inflammation and histologic hepatic fibrosis, while in peripheral blood (PB) samples, KLRG1+ T-cells contain substantially greater levels of cytotoxic molecules (such as granzyme B and perforin), inflammatory cytokines (IFN-γ and tumor necrosis factor α (TNF-α)), and inflammatory chemokine receptors than their KLRG1-negative counterparts [18]. Increased expression of KLRG1 on Treg cells derived from the central nervous system was positively correlated with disease severity in a mouse model of EAE. KLRG1+ Treg cells have a more rapid cell cycle than KLRG1 Tregs and produce more interleukin-10 with the ability to inhibit EAE, thereby modulating disease severity [81]. In SLE patients, the expression level of KLRG1 is significantly elevated in T-cells and is positively correlated with SLE disease activity [80]. Interestingly, in the PB of SLE patients, the expression level of KLRG1 is decreased in NK cells, which negatively correlates with SLE disease activity, but KLRG1 expression increases after in vitro hydroxychloroquine (HCQ) treatment [15]. Although the use of HCQ may be related to the expression level of KLRG1 in NK cells, the mechanism by which this drug works needs further research.

KLRG1 also plays a role in the progression of autoimmune diseases. In the nonobese diabetic mouse model of type 1 diabetes (T1D), KLRG1 is expressed on Foxp3+ Treg cells in the pancreatic islets and plays a role in inhibiting pancreatic autoimmunity, resulting in a decrease in the proliferative and inhibitory functions of Foxp3+ Treg cells. This absence of Foxp3+ Treg cells in pancreatic islets may promote T1D progression, and IL-2 treatment fails to reverse this deficiency [84]. Since KLRG1 inhibits mTOR signaling through the PI3K/AKT pathway, the lack of KLRG1 expression on TCRαβ+ CD4 CD8 double-negative T-cells in ALPS patients leads to overactivity of the mTOR pathway, resulting in abnormal lymphocyte proliferation [56]. In conclusion, these studies suggest that KLRG1 is mostly positively correlated with disease severity in autoimmune diseases [18, 81], can serve as a marker of disease progression in patients with IBM [27, 85] and SLE [80], and has potential as a therapeutic target in patients with IBM [79]. Targeting KLRG1+ lymphocytes may be a promising strategy for developing therapeutic agents for treating autoimmune diseases [18, 79].

Table 2 Expression and role of KLRG1 in autoimmune diseases

KLRG1 in infection

The amount of available data regarding the expression level and role of KLRG1 in infectious diseases, including viral, bacterial, and parasitic infections, is increasing (Table 3) [33, 50, 86, 87]. During infection, the TCR recognizes foreign antigen peptides present on the major histocompatibility complex, followed by the activation and proliferation of T-cells and the regulation of a variety of effector molecules to modulate the antipathogen immune response [88]. As an inhibitory receptor, KLRG1 regulates the activation and function of T-cells and NK cells through various pathways [50, 89, 90]. Sustained antigen stimulation during chronic viral infection leads to T-cell exhaustion characterized by progressive loss of effector function and increased expression of inhibitory immune checkpoint receptors [88, 91]. Research has shown that after infection with viruses, including HCV, human immunodeficiency virus (HIV), mouse cytomegalovirus (MCMV), chronic hepatitis B (CHB), and lymphocytic choriomeningitis virus (LCMV), the expression levels of KLRG1 on virus-specific CD8+ T-cells [92, 93] and NK cells [14, 19, 94] are elevated, and KLRG1 function increases after receiving repeated and sustained antigenic stimulation. However, regarding influenza viruses, only 40–73% of CD8+ cells specific for influenza epitopes are expressing KLRG1 [41].

KLRG1 can inhibit the proliferation and function of immune cells, providing a new target for viral immunotherapy. In HCV infection, KLRG1 inhibits immune cell proliferation and function through the AKT, p16ink4a and p27kip1 pathways, and blocking these pathways may improve vaccine responses [11, 50]. Importantly, one study regarding HCV patients revealed that KLRG1 is a marker for the activation of memory NK cells, which can proliferate more efficiently when restimulated with HCV antigens, thereby facilitating the memory immune response; this finding highlights the potential of KLRG1+ memory NK cells to offer important insights for future vaccine design [94]. Hendrik Streeck et al. reported that the plasma level of soluble E-cad (sE-cad), which can interact with KLRG1+ HIV-1-specific CD8+ T-cells to inhibit IFN-γ secretion and antiviral activity, increased after HIV-1 infection [93]. Ex vivo antibody blockers targeting KLRG1 restored HIV-specific immune responses and the ability of NK cells to kill HIV-infected cells [19, 95]. During the early stage of MCMV infection, KLRG1+ NK cells in the spleen and liver proliferate; the expression of B-cell lymphoma-2 is selectively lost in KLRG1+ NK cells at the late stage of infection, leading to the apoptosis of KLRG1+ NK cells [14, 89, 96]. In addition, KLRG1Ly49H+ NK cells preferentially expand and generate memory NK cells compared to KLRG1+Ly49H+ NK cells, indicating that during MCMV infection, Ly49H+ NK cells lose their potential to produce memory when they reach a mature stage of differentiation [33]. In CHB infection, KLRG1+ NK cells, the number of which is increased in PB and liver samples, can inhibit liver fibrosis by enhancing the apoptosis of activated hepatic stellate cells through the upregulation of expression of tumor necrosis factor-related apoptosis-inducing ligands. This antifibrotic function of KLRG1+ NK cells provides a new therapeutic approach for treating liver fibrosis in patients with CHB [97].

KLRG1 has also been detected in a few bacterial infections, such as Mycobacterium tuberculosis (Mtb) and Helicobacter pylori (H. pylori) [90, 98]. During Mtb infection, KLRG1 is overexpressed on lung CD4+ T-cells, and these KLRG1+CD4+ T-cells secrete significantly greater amounts of IFN-γ, IL-2, and tumor necrosis factor-alpha than do KLRG1CD4+ T-cells [90]. Increased KLRG1+CD4+ T-cells may negatively impact immunity by enhancing stromal adherence and restricting the access of terminal effector cells to the infection site [90]. Blockade of KLRG1 enhances AKT signaling, reduces lung burden, and prolongs survival time after infection; thus, KLRG1 is a potential target for antituberculosis immunotherapy [99]. However, Park et al. conducted a transcriptomic analysis of H. pylori-infected cells before and after the use of kimchi extract and reported that KLRG1 gene expression significantly decreased during H. pylori infection but increased after nutritional supplementation with kimchi extracts [98]. This is the first study to identify KLRG1 in H. pylori infection, and its role still needs further investigation.

Parasitic infection is a type of disease in which parasites invade and cause infection in humans or animals, leading to persistent infection mainly by inhibition of the immune response and generation of immune tolerance [100]. KLRG1 expression is upregulated during infection with several parasitic protozoans, including Toxoplasma gondii, Nippostrongylus brasiliensis, and Leishmania [32, 101]. This increase may inhibit the immune function of T-cells and limit the clearance of T. gondii [87, 102]. KLRG1 may play a role in immune regulation and tolerance by inhibiting immune cell proliferation and cytokine production [100]. KLRG1 can bind to ligands on the surface of ILC-2s, inhibit ILC-2 proliferation and activation, and reduce the ability of ILC-2s to produce cytokines, thereby decreasing the immune responses of ILC-2s to parasitic infection [49]. Antibody blockade of PD-1 during N. brasiliensis infection increases the number of KLRG1+ ILC-2s, which enhances the protective function of ILC-2s in parasitic infections and reduces the disease burden [72]. In aged visceral Leishmania-infected mice, the expression of KLRG1 is increased on hepatic and splenic CD4+ and CD8+ T-cells, leading to decreased IFN-γ production and reduced proliferative ability of T-cells, which suggests that senescence may increase the susceptibility of patients to visceral Leishmania infection [101]. In summary, KLRG1 expression is increased on immune cells after repeated and sustained antigenic stimulation and can serve as a marker for assessing the extent of infection in patients infected with HCV and Mtb [92, 99]. KLRG1 expression can also lead to persistent infections by inhibiting the proliferation and function of immune cells and can serve as a potential therapeutic target in patients with HCV, HIV, and Mtb [92, 95, 99]. Inhibition of KLRG1 expression may become a new method for treating infectious diseases [11, 86].

Table 3 Expression and role of KLRG1 in infectious diseases

KLRG1 in tumors

As protective factors of the human immune system, immune checkpoint molecules are critical for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues [103]. In tumor cells, the dysregulation of immune checkpoint proteins is an important mechanism of tumor immune resistance. When immune checkpoint molecules are overexpressed or overactivated, immune function is inhibited [104]. Research has shown that KLRG1 plays an important role in many types of tumors, including solid and malignant hematological tumors. KLRG1 can bind to ligands and play an important role in tumor development by regulating lymphocyte activity, inhibiting cytokine secretion, and inducing apoptosis to suppress the immune response [14, 50, 105]. In the tumor microenvironment, KLRG1 can inhibit the antitumor immune response and promote tumor escape [23, 105]. The expression level of KLRG1 is also significantly correlated with the immunotherapy responses of patients with various diseases and can serve as a biomarker for the prognoses of patients with tumors (Table 4) [16, 106, 107].

KLRG1 in solid tumors

In patients with solid tumors, KLRG1 may affect the proliferation of tumor cells or participate in the regulation of tumor immune escape and immune tolerance by interacting with cell surface receptor signaling pathways [16, 23, 108]. Compared to that in healthy populations, the expression of KLRG1 is increased in T-cells in patients with solid tumors such as those of breast and colorectal cancer (CRC) [8, 26, 107, 109] and decreased in NK cells in melanoma tumor tissues in mice and in lung tumor cells in patients with lung adenocarcinoma (LUAD) [16, 22, 28, 110]. The expression level of KLRG1 is positively correlated with antigen-presenting cell infiltration in LUAD, and Dietmar et al. reported that KLRG1+ effector CD8+ T-cells can differentiate into memory T-cells to promote antitumor immunity, which suggests that KLRG1 could be used in the development of mRNA vaccines [22, 111]. However, this antitumor effect of KLRG1 expression on tumor cells contradicts its protumor effect on immune cells [23]. Yang et al. reported that the expression of KLRG1 was significantly lower in lung tumor cells from LUAD patients than in those from healthy controls and that a decrease in KLRG1 expression enhanced the proliferation of LUAD cells. In addition, the expression of KLRG1 is positively correlated with the efficacy of immune checkpoint inhibitors, and patients with high KLRG1 expression have a better prognosis, which suggests that KLRG1 may become a prognostic biomarker for LUAD patients [16]. Yang et al. hypothesized that this contradiction may result from the competitive binding of KLRG1 on tumor cells to the ligand E-cad, which decreases the inhibitory effect of KLRG1 on T-cells and NK cells [16]. Therefore, in the study of the role of KLRG1 on tumor cells, KLRG1 expression levels on the surfaces of both immune cells and tumor cells should be measured.

KLRG1 can inhibit the antitumor activity of immune cells and promote tumor metastasis. In breast cancer patients, Yamauchi et al. reported that the interaction of E-cad and KLRG1 inhibits antibody-dependent cell-mediated cytotoxicity (ADCC), rendering human epidermal growth factor receptor-2-expressing tumor cells resistant to trastuzumab treatment. Removal of KLRG1-positive peripheral blood mononuclear cells can enhance trastuzumab-mediated ADCC activity and improve therapeutic efficacy, but the means by which this method enhances ADCC activity still needs further study [108]. NK cells have effective antitumor and antimetastatic activities [112]. However, breast cancer cells can reprogram tumor-exposed NK (teNK) cells to promote metastatic colony formation. Targeting KLRG1 expressed on teNK cells eliminates the metastasis-promoting effects of teNK cells and decreases colony formation, providing a new approach for preventing or treating metastatic tumors [8, 26]. Necroptosis is a form of necrotic programmed cell death that frequently occurs in advanced solid tumors and can inhibit the antitumor activities of T-cells and promote breast cancer metastasis by synergistically inhibiting the KLRG1 receptor [113]. In a mouse model of breast cancer, antibody neutralization of KLRG1 significantly increased the antitumor activities of tumor-infiltrating T-cells and PB T-cells and significantly reduced lung metastasis [24]. In mouse melanoma-related NK cells, a decrease in KLRG1 expression leads to a decreased proliferative capacity of intratumoral NK cells [110].

In addition, the expression level of KLRG1 is positively correlated with therapeutic outcome, which suggests that KLRG1 could serve as a marker to monitor the antitumor immune response induced by this therapy [28]. Antibodies that block CTLA-4 expression or activate 4-1BB both enhance the body’s antitumor immunity but fail to cure poorly immunogenic B16 melanomas when used alone [114, 115]. Curran et al. reported that the combined use of these two antibodies led to high expression of KLRG1 on tumor-infiltrating effector T-cells in mice, which promoted an immune-rejection response to melanoma [28]. In CRC patients, the mRNA expression level of KLRG1 was significantly greater in tumor tissues than in paired normal tissues and tended to increase in the advanced stages of the disease [107]. Furthermore, KLRG1+ cytotoxic T-cells are enriched in CRC patients with a good prognosis [109], and CD27lowKLRG1+ NK cells protect T-box expressed in T-cells (T-bet)-deficient mice from pulmonary metastatic colorectal carcinoma [116]. Overall, KLRG1 can inhibit the antitumor activities of immune cells, promote tumor metastasis, and lead to immune dysfunction in patients. KLRG1 in LUAD and melanoma can serve as a marker for detecting the response to treatment with immune checkpoint inhibitors [16, 28] and has the potential to be a therapeutic target in breast cancer, melanoma, and CRC [8, 22, 116].

KLRG1 in hematological malignancies

HMs are a group of hematopoietic diseases characterized by a high degree of malignancy, complex treatment, and poor prognosis. KLRG1 expression is increased on a variety of immune cells in patients with a variety of HMs, including chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), acute myeloid leukemia (AML), and multiple myeloma (MM) [117,118,119]. KLRG1-positive cells have impaired proliferation ability and can bind to ligands to inhibit CD8+ T-cell effector function, leading to immune dysfunction in patients [117,118,119,120,121]. In CLL patients, the expression levels of KLRG1+CD8+ T-cells and plasma sE-cad are increased. Based on data obtained by Streeck et al. studying HIV, these two proteins may interact to inhibit KLRG1+CD8+ T-cell effector function, leading to immune dysfunction in CLL patients [117]. In patients with FL, CD8+ T-cells lose their proliferative capacity after differentiating into KLRG1+CD127CD8+ T-cells, which have a greater capacity to produce cytokines but lower activity than KLRG1CD127+CD8+ T-cells. Therefore, the modulation of CD8+ T-cell differentiation in FL by PI3K inhibitors may promote a more effective antitumor immune response and thus improve the clinical prognosis of lymphoma patients [121].

KLRG1 may also be a marker for monitoring antitumor responses induced by anti-4-1BB mAbs. In an Em-myc lymphoma model, anti-4-1BB mAb treatment induces KLRG1 expression in CD8+ T-cells [122]. A study of a combination treatment for AML including a vaccine and an anti-4-1BB mAb revealed that treatment-induced KLRG1+ effector CD8+ T-cells were most effective for controlling disease progression [123]. In addition, in tumor-bearing mice, the migration of KLRG1+ NK cells to the bone marrow is impaired and regulated by C-X-C motif chemokine receptor 3, resulting in a rapid and selective decrease in the number of KLRG1 NK cells with potent effector functions in the bone marrow, which contributes to tumor escape from NK cell-mediated immune surveillance [124]. In conclusion, KLRG1 has a similar role in hematologic malignancies as in solid tumors.

Table 4 Expression and role of KLRG1 in tumors

KLRG1 as a tool for immunotherapy

The direct recognition, rapid activation, and cytotoxicity of KLRG1 on cancer cells make it an attractive tool for cancer immunotherapy, and this has recently been extensively reviewed [5, 70]. KLRG1 has demonstrated significant antitumor and inhibitory effects on tumor growth in a wide range of malignant tumors, while KLRG1-targeted inhibitors have also been developed as tumor immunotherapies and have been a popular area of research in immunotherapy [8, 23,24,25].

The absence of KLRG1 signaling alone significantly reduced the growth of melanoma and breast cancer tumors in mouse lungs. In a 4T1 breast cancer model, an anti-KLRG1 antibody inhibited the binding of mouse E-cad to KLRG1 and significantly reduced lung metastasis [8]. In a mouse model of breast cancer, antibody neutralization of KLRG1 reduced the formation of tumor colonies [26], significantly increased the antitumor activity of tumor-infiltrating cells and peripheral T-cells, and reduced lung metastasis [24].

In addition, combinations of checkpoint blockade therapies have shown effectiveness in many different types of cancer [126]. Tregs can hinder T-cell function in various tumors and inhibit antitumor immunity [127, 128]. In a melanoma mouse model, the use of an anti-KLRG1 antibody alone moderately depleted intratumoral Tregs but not peripheral Tregs, which prevented the autoimmune side effects caused by systemic depletion of Tregs [25, 129]. Administration of a bromodomain inhibitor also partially depleted intratumoral Tregs, and when this treatment is combined with anti-KLRG1 antibody, tumor-infiltrating CD8+ T-cells express higher levels of granzyme B and IFN-γ, significantly improving the antitumor response [25]. KLRG1 blockade works synergistically with PD-1 checkpoint therapy, which increases the frequency and maturation of CD8+ T-cells and NK cells in the tumor microenvironment, promoting antitumor immunity against melanoma tumor growth [23]. In a mouse model of breast cancer, the combination of an anti-KLRG1 antibody with a DNA methyltransferase inhibitor further reduced the metastatic potential of breast cancer and effectively prevented metastatic recurrence compared to use of the antibody alone [26]. Tumors that do not respond to anti-PD-1 monoclonal antibody therapy alone may still benefit from combination therapy with KLRG1 blockade [23]. In MC38 colon cancer and B16F10 melanoma models, combination therapy of anti-KLRG1 and anti-PD-1 antibodies inhibited tumor growth and synergistically reduced tumor volume more than treatment with anti-KLRG1 or anti-PD-1 antibody controls alone [8].


Studies targeting KLRG1 have shown that KLRG1 not only serves as a marker of T-cell senescence [65] but also increases with disease severity in autoimmune, viral infections and cancer, and can serve as a biomarker for assessing disease progression and prognosis [16, 27, 80, 92, 99]. Recently, researchers have revealed that targeting cells expressing KLRG1 has the potential to control disease progression by attenuating the inhibitory effects of antitumor responses, thereby benefiting the host. As discussed above, KLRG1-related signal transduction occurs mainly through the PI3K/AKT, KLRG1/AMPK, and p16ink4a/p27kip1 pathways to inhibit the cytotoxicity and proliferation of NK cells and T-cells, cytokine secretion, and telomerase expression and activity [10,11,12]. More work is needed to investigate the roles of additional regulatory mechanisms or regulatory mechanisms between different inhibitory receptors in diverse cellular contexts to further explain why tumors that are insensitive to other inhibitor therapies could still benefit from combination therapy with an anti-KLRG1 antibody. Indeed, the combination of anti-KLRG1 with other inhibitors can improve the antitumor response in mice with melanoma, further reducing the metastatic potential of breast cancer and effectively preventing metastatic recurrence [23, 26]. Although there are no approved anti-KLRG1 drugs on the market, Ulviprubart (ABC008), an anti-KLRG1 drug product developed by Abcuro for the treatment of IBM, has progressed to clinical phase 2/3 and has been granted orphan drug status by the U.S. Food and Drug Administration and the European Medicines Agency [27]. The study of ABC015 for the treatment of cancer is in the preclinical stage. It is foreseeable that the emergence of future anti-KLRG1 drugs will lead to the development of new treatment strategies for tumor suppressor receptor immunotherapy.

Data availability

No datasets were generated or analysed during the current study.



Killer cell lectin-like receptor G1


Immunoreceptor tyrosine-based inhibitory motif


Natural killer


Regulatory T


Antigen-presenting cells


T cell receptor


AMP-responsive protein kinase


Hematological malignancies


Monoclonal antibody


Inclusion body myositis


Mouse KLRG1


Human KLRG1




Programmed cell death protein 1


Phosphoinositide 3-kinase








Type 2 innate lymphoid cells

PIP2 :

Phosphatidylinositol (4,5) bisphosphate

PIP3 :

Phosphatidylinositol (3,4,5) bisphosphate


Mammalian target of rapamycin


Hepatitis C virus


Forkhead box O


Cyclin-dependent kinase


Protein Phosphatase 2 C


Src Homology 2-containing Inositol Phosphatase-1


Src homology-2-containing protein tyrosine phosphatase 2






Cytotoxic T lymphocyte-associated protein 4


B lymphocyte-induced maturation protein 1


Primary biliary cholangitis


Type 1 diabetes


Systemic lupus erythematosus


Experimental autoimmune encephalomyelitis


Autoimmune lymphoproliferative syndrome


Peripheral blood


Healthy control


Tumor necrosis factorα




Human immunodeficiency virus


Mouse cytomegalovirus


Chronic hepatitis B


Lymphocytic choriomeningitis virus


Soluble E-cadherin


Mycobacterium tuberculosis

H. Pylori:

Helicobacter pylori


Colorectal cancer


Lung adenocarcinoma


Antibody-dependent cell-mediated cytotoxicity


Tumor-exposed NK


T-box expressed in T cells


Chronic lymphocytic leukemia


Follicular lymphoma


Acute myeloid leukemia


Multiple myeloma


  1. Abramson J, Xu R, Pecht I. An unusual inhibitory receptor–the mast cell function-associated antigen (MAFA). Mol Immunol. 2002;38(16–18):1307–13.

    Article  CAS  PubMed  Google Scholar 

  2. Butcher S, Arney KL, Cook GP. MAFA-L, an ITIM-containing receptor encoded by the human NK cell gene complex and expressed by basophils and NK cells. Eur J Immunol. 1998;28(11):3755–62.

    Article  CAS  PubMed  Google Scholar 

  3. Blaser C, Kaufmann M, Pircher H. Virus-activated CD8 T cells and lymphokine-activated NK cells express the mast cell function-associated antigen, an inhibitory C-type lectin. J Immunol. 1998;161(12):6451–4.

    Article  CAS  PubMed  Google Scholar 

  4. Beyersdorf N, Ding X, Tietze JK, Hanke T. Characterization of mouse CD4 T cell subsets defined by expression of KLRG1. Eur J Immunol. 2007;37(12):3445–54.

    Article  CAS  PubMed  Google Scholar 

  5. Borys SM, Bag AK, Brossay L, Adeegbe DO. The Yin and Yang of Targeting KLRG1(+) Tregs and Effector cells. Front Immunol. 2022;13:894508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Corral L, Hanke T, Vance RE, Cado D, Raulet DH. NK cell expression of the killer cell lectin-like receptor G1 (KLRG1), the mouse homolog of MAFA, is modulated by MHC class I molecules. Eur J Immunol. 2000;30(3):920–30.

    Article  CAS  PubMed  Google Scholar 

  7. Huntington ND, Tabarias H, Fairfax K, Brady J, Hayakawa Y, Degli-Esposti MA, et al. NK cell maturation and peripheral homeostasis is associated with KLRG1 up-regulation. J Immunol. 2007;178(8):4764–70.

    Article  CAS  PubMed  Google Scholar 

  8. Greenberg SA, Kong SW, Thompson E, Gulla SV. Co-inhibitory T cell receptor KLRG1: human cancer expression and efficacy of neutralization in murine cancer models. Oncotarget. 2019;10(14):1399–406.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Ito M, Maruyama T, Saito N, Koganei S, Yamamoto K, Matsumoto N. Killer cell lectin-like receptor G1 binds three members of the classical cadherin family to inhibit NK cell cytotoxicity. J Exp Med. 2006;203(2):289–95.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Müller-Durovic B, Lanna A, Covre LP, Mills RS, Henson SM, Akbar AN. Killer cell lectin-like receptor G1 inhibits NK Cell function through activation of Adenosine 5’-Monophosphate-activated protein kinase. J Immunol. 2016;197(7):2891–9.

    Article  PubMed  Google Scholar 

  11. Shi L, Wang JM, Ren JP, Cheng YQ, Ying RS, Wu XY, et al. KLRG1 impairs CD4 + T cell responses via p16ink4a and p27kip1 pathways: role in hepatitis B vaccine failure in individuals with hepatitis C virus infection. J Immunol. 2014;192(2):649–57.

    Article  CAS  PubMed  Google Scholar 

  12. Van den Bossche J, Malissen B, Mantovani A, De Baetselier P, Van Ginderachter JA. Regulation and function of the E-cadherin/catenin complex in cells of the monocyte-macrophage lineage and DCs. Blood. 2012;119(7):1623–33.

    Article  PubMed  Google Scholar 

  13. Guthmann MD, Tal M, Pecht I. A new member of the C-type lectin family is a modulator of the mast cell secretory response. Int Arch Allergy Immunol. 1995;107(1–3):82–6.

    Article  CAS  PubMed  Google Scholar 

  14. Robbins SH, Nguyen KB, Takahashi N, Mikayama T, Biron CA, Brossay L. Cutting edge: inhibitory functions of the killer cell lectin-like receptor G1 molecule during the activation of mouse NK cells. J Immunol. 2002;168(6):2585–9.

    Article  CAS  PubMed  Google Scholar 

  15. Novelli L, Barbati C, Capuano C, Recalchi S, Ceccarelli F, Vomero M, et al. KLRG1 is reduced on NK cells in SLE patients, inversely correlates with disease activity and is modulated by hydroxychloroquine in vitro. Lupus. 2023;32(4):549–59.

    Article  CAS  PubMed  Google Scholar 

  16. Yang X, Zheng Y, Han Z, Zhang X. Functions and clinical significance of KLRG1 in the development of lung adenocarcinoma and immunotherapy. BMC Cancer. 2021;21(1):752.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Eberl M, Engel R, Aberle S, Fisch P, Jomaa H, Pircher H. Human Vgamma9/Vdelta2 effector memory T cells express the killer cell lectin-like receptor G1 (KLRG1). J Leukoc Biol. 2005;77(1):67–70.

    Article  CAS  PubMed  Google Scholar 

  18. Li Y, Li B, You Z, Zhang J, Wei Y, Li Y, et al. Cytotoxic KLRG1 expressing lymphocytes invade portal tracts in primary biliary cholangitis. J Autoimmun. 2019;103:102293.

    Article  CAS  PubMed  Google Scholar 

  19. Astorga-Gamaza A, Perea D, Sanchez-Gaona N, Calvet-Mirabent M, Gallego-Cortés A, Grau-Expósito J, et al. KLRG1 expression on natural killer cells is associated with HIV persistence, and its targeting promotes the reduction of the viral reservoir. Cell Rep Med. 2023;4(10):101202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Li M-H, Yin W-W, Zhang Q-F, Liu Q, Li Y-L, Shao J-Y, et al. KLRG1 impairs antiviral immunity of NK-cell in individuals with chronic Hepatitis B Virus infection via the akt pathway. J Hepatol. 2017;1(66):S539–40.

    Article  Google Scholar 

  21. Assatova B, Willim R, Trevisani C, Haskett G, Kariya KM, Chopra K et al. KLRG1 cell depletion as a Novel Therapeutic Strategy in patients with mature T-cell lymphoma subtypes. Clin Cancer Res. 2024.

  22. Xu R, Lu T, Zhao J, Wang J, Peng B, Zhang L. Identification of Tumor antigens and Immune subtypes in Lung Adenocarcinoma for mRNA Vaccine Development. Front Cell Dev Biol. 2022;10:815596.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Tata A, Dodard G, Fugère C, Leget C, Ors M, Rossi B, et al. Combination blockade of KLRG1 and PD-1 promotes immune control of local and disseminated cancers. Oncoimmunology. 2021;10(1):1933808.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Liu Z, Choksi S, Kwon HJ, Jiao D, Liu C, Liu ZG. Tumor necroptosis-mediated shedding of cell surface proteins promotes metastasis of breast cancer by suppressing anti-tumor immunity. Breast Cancer Res. 2023;25(1):10.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Noyes D, Bag A, Oseni S, Semidey-Hurtado J, Cen L, Sarnaik AA et al. Tumor-associated Tregs obstruct antitumor immunity by promoting T cell dysfunction and restricting clonal diversity in tumor-infiltrating CD8 + T cells. J Immunother Cancer. 2022;10(5).

  26. Chan IS, Knútsdóttir H, Ramakrishnan G, Padmanaban V, Warrier M, Ramirez JC et al. Cancer cells educate natural killer cells to a metastasis-promoting cell state. J Cell Biol. 2020;219(9).

  27. Goel N, Needham M, Soler-Ferran D, Cotreau MM, Escobar J, Greenberg S, POS1342 DEPLETION, OF KLRG1 + T CELLS IN A FIRST-IN-HUMAN CLINICAL TRIAL OF ABC008 IN INCLUSION BODY MYOSITIS (IBM). Ann Rheum Dis. 2022;81(Suppl 1):10083–9.

    Article  Google Scholar 

  28. Curran MA, Kim M, Montalvo W, Al-Shamkhani A, Allison JP. Combination CTLA-4 blockade and 4-1BB activation enhances tumor rejection by increasing T-cell infiltration, proliferation, and cytokine production. PLoS ONE. 2011;6(4):e19499.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ortega E, Schneider H, Pecht I. Possible interactions between the fc epsilon receptor and a novel mast cell function-associated antigen. Int Immunol. 1991;3(4):333–42.

    Article  CAS  PubMed  Google Scholar 

  30. Voehringer D, Koschella M, Pircher H. Lack of proliferative capacity of human effector and memory T cells expressing killer cell lectinlike receptor G1 (KLRG1). Blood. 2002;100(10):3698–702.

    Article  CAS  PubMed  Google Scholar 

  31. Zeng X, Zheng M, Liu T, Bahabayi A, Kang R, Xu Q, et al. Changes in the expression of T-cell factor-1 in follicular helper T cells reflect the condition of systemic lupus erythematosus patients. Int Immunopharmacol. 2022;108:108877.

    Article  CAS  PubMed  Google Scholar 

  32. Robbins SH, Terrizzi SC, Sydora BC, Mikayama T, Brossay L. Differential regulation of killer cell lectin-like receptor G1 expression on T cells. J Immunol. 2003;170(12):5876–85.

    Article  CAS  PubMed  Google Scholar 

  33. Kamimura Y, Lanier LL. Homeostatic control of memory cell progenitors in the natural killer cell lineage. Cell Rep. 2015;10(2):280–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Voehringer D, Kaufmann M, Pircher H. Genomic structure, alternative splicing, and physical mapping of the killer cell lectin-like receptor G1 gene (KLRG1), the mouse homologue of MAFA. Immunogenetics. 2001;52(3–4):206–11.

    Article  CAS  PubMed  Google Scholar 

  35. Bocek P Jr., Guthmann MD, Pecht I. Analysis of the genes encoding the mast cell function-associated antigen and its alternatively spliced transcripts. J Immunol. 1997;158(7):3235–43.

    Article  CAS  PubMed  Google Scholar 

  36. Lamers MB, Lamont AG, Williams DH. Human MAFA has alternatively spliced variants. Biochim Biophys Acta. 1998;1399(2–3):209–12.

    Article  CAS  PubMed  Google Scholar 

  37. Guthmann MD, Tal M, Pecht I. A secretion inhibitory signal transduction molecule on mast cells is another C-type lectin. Proc Natl Acad Sci U S A. 1995;92(20):9397–401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Schwartzkopff S, Gründemann C, Schweier O, Rosshart S, Karjalainen KE, Becker KF, et al. Tumor-associated E-cadherin mutations affect binding to the killer cell lectin-like receptor G1 in humans. J Immunol. 2007;179(2):1022–9.

    Article  CAS  PubMed  Google Scholar 

  39. Hofmann M, Schweier O, Pircher H. Different inhibitory capacities of human and mouse KLRG1 are linked to distinct disulfide-mediated oligomerizations. Eur J Immunol. 2012;42(9):2484–90.

    Article  CAS  PubMed  Google Scholar 

  40. Li Y, Hofmann M, Wang Q, Teng L, Chlewicki LK, Pircher H, et al. Structure of natural killer cell receptor KLRG1 bound to E-cadherin reveals basis for MHC-independent missing self recognition. Immunity. 2009;31(1):35–46.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Ibegbu CC, Xu YX, Harris W, Maggio D, Miller JD, Kourtis AP. Expression of killer cell lectin-like receptor G1 on antigen-specific human CD8 + T lymphocytes during active, latent, and resolved infection and its relation with CD57. J Immunol. 2005;174(10):6088–94.

    Article  CAS  PubMed  Google Scholar 

  42. Henson SM, Franzese O, Macaulay R, Libri V, Azevedo RI, Kiani-Alikhan S, et al. KLRG1 signaling induces defective akt (ser473) phosphorylation and proliferative dysfunction of highly differentiated CD8 + T cells. Blood. 2009;113(26):6619–28.

    Article  CAS  PubMed  Google Scholar 

  43. Rosshart S, Hofmann M, Schweier O, Pfaff AK, Yoshimoto K, Takeuchi T, et al. Interaction of KLRG1 with E-cadherin: new functional and structural insights. Eur J Immunol. 2008;38(12):3354–64.

    Article  CAS  PubMed  Google Scholar 

  44. Tessmer MS, Fugere C, Stevenaert F, Naidenko OV, Chong HJ, Leclercq G, et al. KLRG1 binds cadherins and preferentially associates with SHIP-1. Int Immunol. 2007;19(4):391–400.

    Article  CAS  PubMed  Google Scholar 

  45. Banh C, Fugère C, Brossay L. Immunoregulatory functions of KLRG1 cadherin interactions are dependent on forward and reverse signaling. Blood. 2009;114(26):5299–306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Nakamura S, Kuroki K, Ohki I, Sasaki K, Kajikawa M, Maruyama T, et al. Molecular basis for E-cadherin recognition by killer cell lectin-like receptor G1 (KLRG1). J Biol Chem. 2009;284(40):27327–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Gründemann C, Bauer M, Schweier O, von Oppen N, Lässing U, Saudan P, et al. Cutting edge: identification of E-cadherin as a ligand for the murine killer cell lectin-like receptor G1. J Immunol. 2006;176(3):1311–5.

    Article  PubMed  Google Scholar 

  48. Lou C, Wu K, Shi J, Dai Z, Xu Q. N-cadherin protects oral cancer cells from NK cell killing in the circulation by inducing NK cell functional exhaustion via the KLRG1 receptor. J Immunother Cancer. 2022;10(9).

  49. Salimi M, Barlow JL, Saunders SP, Xue L, Gutowska-Owsiak D, Wang X, et al. A role for IL-25 and IL-33-driven type-2 innate lymphoid cells in atopic dermatitis. J Exp Med. 2013;210(13):2939–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Wang JM, Cheng YQ, Shi L, Ying RS, Wu XY, Li GY, et al. KLRG1 negatively regulates natural killer cell functions through the akt pathway in individuals with chronic hepatitis C virus infection. J Virol. 2013;87(21):11626–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Xu R, Abramson J, Fridkin M, Pecht I. SH2 domain-containing inositol polyphosphate 5’-phosphatase is the main mediator of the inhibitory action of the mast cell function-associated antigen. J Immunol. 2001;167(11):6394–402.

    Article  CAS  PubMed  Google Scholar 

  52. Revathidevi S, Munirajan AK. Akt in cancer: Mediator and more. Semin Cancer Biol. 2019;59:80–91.

    Article  CAS  PubMed  Google Scholar 

  53. Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C, González-Barón M. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 2004;30(2):193–204.

    Article  PubMed  Google Scholar 

  54. Carnero A, Paramio JM. The PTEN/PI3K/AKT pathway in vivo, Cancer Mouse models. Front Oncol. 2014;4:252.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Donahue AC, Fruman DA. PI3K signaling controls cell fate at many points in B lymphocyte development and activation. Semin Cell Dev Biol. 2004;15(2):183–97.

    Article  CAS  PubMed  Google Scholar 

  56. Völkl S, Rensing-Ehl A, Allgäuer A, Schreiner E, Lorenz MR, Rohr J, et al. Hyperactive mTOR pathway promotes lymphoproliferation and abnormal differentiation in autoimmune lymphoproliferative syndrome. Blood. 2016;128(2):227–38.

    Article  PubMed  Google Scholar 

  57. Yao ZQ, Eisen-Vandervelde A, Ray S, Hahn YS. HCV core/gC1qR interaction arrests T cell cycle progression through stabilization of the cell cycle inhibitor p27Kip1. Virology. 2003;314(1):271–82.

    Article  CAS  PubMed  Google Scholar 

  58. Roy SK, Srivastava RK, Shankar S. Inhibition of PI3K/AKT and MAPK/ERK pathways causes activation of FOXO transcription factor, leading to cell cycle arrest and apoptosis in pancreatic cancer. J Mol Signal. 2010;5:10.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Ghamar Talepoor A, Doroudchi M. Immunosenescence in atherosclerosis: a role for chronic viral infections. Front Immunol. 2022;13:945016.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Salminen A, Kaarniranta K, Kauppinen A. Age-related changes in AMPK activation: role for AMPK phosphatases and inhibitory phosphorylation by upstream signaling pathways. Ageing Res Rev. 2016;28:15–26.

    Article  CAS  PubMed  Google Scholar 

  61. Lanna A, Henson SM, Escors D, Akbar AN. The kinase p38 activated by the metabolic regulator AMPK and scaffold table 1 drives the senescence of human T cells. Nat Immunol. 2014;15(10):965–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Bouchentouf M, Forner KA, Cuerquis J, Michaud V, Zheng J, Paradis P, et al. Induction of cardiac angiogenesis requires killer cell lectin-like receptor 1 and α4β7 integrin expression by NK cells. J Immunol. 2010;185(11):7014–25.

    Article  CAS  PubMed  Google Scholar 

  63. Kim KH, Choi A, Kim SH, Song H, Jin S, Kim K, et al. Neural-cadherin influences the homing of terminally differentiated memory CD8 T cells to the Lymph nodes and Bone Marrow. Mol Cells. 2021;44(11):795–804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Reiss K, Maretzky T, Ludwig A, Tousseyn T, de Strooper B, Hartmann D, et al. ADAM10 cleavage of N-cadherin and regulation of cell-cell adhesion and beta-catenin nuclear signalling. Embo j. 2005;24(4):742–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Voehringer D, Blaser C, Brawand P, Raulet DH, Hanke T, Pircher H. Viral infections induce abundant numbers of senescent CD8 T cells. J Immunol. 2001;167(9):4838–43.

    Article  CAS  PubMed  Google Scholar 

  66. Ouyang Q, Wagner WM, Voehringer D, Wikby A, Klatt T, Walter S, et al. Age-associated accumulation of CMV-specific CD8 + T cells expressing the inhibitory killer cell lectin-like receptor G1 (KLRG1). Exp Gerontol. 2003;38(8):911–20.

    Article  CAS  PubMed  Google Scholar 

  67. Soto-Heredero G, Gómez de Las Heras MM, Escrig-Larena JI, Mittelbrunn M. Extremely differentiated T cell subsets contribute to tissue deterioration during aging. Annu Rev Immunol. 2023;41:181–205.

    Article  CAS  PubMed  Google Scholar 

  68. Joshi NS, Cui W, Chandele A, Lee HK, Urso DR, Hagman J, et al. Inflammation directs memory precursor and short-lived effector CD8(+) T cell fates via the graded expression of T-bet transcription factor. Immunity. 2007;27(2):281–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Remmerswaal EBM, Hombrink P, Nota B, Pircher H, Ten Berge IJM, van Lier RAW, et al. Expression of IL-7Rα and KLRG1 defines functionally distinct CD8(+) T-cell populations in humans. Eur J Immunol. 2019;49(5):694–708.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Henson SM, Akbar AN. KLRG1–more than a marker for T cell senescence. Age (Dordr). 2009;31(4):285–91.

    Article  CAS  PubMed  Google Scholar 

  71. Cheng G, Yuan X, Tsai MS, Podack ER, Yu A, Malek TR. IL-2 receptor signaling is essential for the development of Klrg1 + terminally differentiated T regulatory cells. J Immunol. 2012;189(4):1780–91.

    Article  CAS  PubMed  Google Scholar 

  72. Taylor S, Huang Y, Mallett G, Stathopoulou C, Felizardo TC, Sun MA, et al. PD-1 regulates KLRG1(+) group 2 innate lymphoid cells. J Exp Med. 2017;214(6):1663–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Thaventhiran JE, Hoffmann A, Magiera L, de la Roche M, Lingel H, Brunner-Weinzierl M, et al. Activation of the Hippo pathway by CTLA-4 regulates the expression of Blimp-1 in the CD8 + T cell. Proc Natl Acad Sci U S A. 2012;109(33):E2223–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Kallies A, Xin A, Belz GT, Nutt SL. Blimp-1 transcription factor is required for the differentiation of effector CD8(+) T cells and memory responses. Immunity. 2009;31(2):283–95.

    Article  CAS  PubMed  Google Scholar 

  75. Schweier O, Hofmann M, Pircher H. KLRG1 activity is regulated by association with the transferrin receptor. Eur J Immunol. 2014;44(6):1851–6.

    Article  CAS  PubMed  Google Scholar 

  76. Wang L, Wang FS, Gershwin ME. Human autoimmune diseases: a comprehensive update. J Intern Med. 2015;278(4):369–95.

    Article  CAS  PubMed  Google Scholar 

  77. Burke KP, Patterson DG, Liang D, Sharpe AH. Immune checkpoint receptors in autoimmunity. Curr Opin Immunol. 2023;80:102283.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Huang C, Zhu HX, Yao Y, Bian ZH, Zheng YJ, Li L, et al. Immune checkpoint molecules. Possible future therapeutic implications in autoimmune diseases. J Autoimmun. 2019;104:102333.

    Article  CAS  PubMed  Google Scholar 

  79. Greenberg SA, Pinkus JL, Kong SW, Baecher-Allan C, Amato AA, Dorfman DM. Highly differentiated cytotoxic T cells in inclusion body myositis. Brain. 2019;142(9):2590–604.

    Article  PubMed  Google Scholar 

  80. Kalim H, Wahono CS, Permana BPO, Pratama MZ, Handono K. Association between senescence of T cells and disease activity in patients with systemic lupus erythematosus. Reumatologia. 2021;59(5):292–301.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Tauro S, Nguyen P, Li B, Geiger TL. Diversification and senescence of Foxp3 + regulatory T cells during experimental autoimmune encephalomyelitis. Eur J Immunol. 2013;43(5):1195–207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Matsubara S, Suzuki S, Komori T. Immunohistochemical Phenotype of T Cells Invading Muscle in inclusion body myositis. J Neuropathol Exp Neurol. 2022;81(10):825–35.

    Article  CAS  PubMed  Google Scholar 

  83. Goyal NA, Coulis G, Duarte J, Farahat PK, Mannaa AH, Cauchii J, et al. Immunophenotyping of inclusion body myositis blood T and NK cells. Neurology. 2022;98(13):e1374–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Kornete M, Mason E, Istomine R, Piccirillo CA. KLRG1 expression identifies short-lived Foxp3(+) T(reg) effector cells with functional plasticity in islets of NOD mice. Autoimmunity. 2017;50(6):354–62.

    Article  CAS  PubMed  Google Scholar 

  85. Vogt S, Kleefeld F, Preusse C, Arendt G, Bieneck S, Brunn A, et al. Morphological and molecular comparison of HIV-associated and sporadic inclusion body myositis. J Neurol. 2023;270(9):4434–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Heffner M, Fearon DT. Loss of T cell receptor-induced Bmi-1 in the KLRG1(+) senescent CD8(+) T lymphocyte. Proc Natl Acad Sci U S A. 2007;104(33):13414–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Harms Pritchard G, Hall AO, Christian DA, Wagage S, Fang Q, Muallem G, et al. Diverse roles for T-bet in the effector responses required for resistance to infection. J Immunol. 2015;194(3):1131–40.

    Article  CAS  PubMed  Google Scholar 

  88. Belk JA, Daniel B, Satpathy AT. Epigenetic regulation of T cell exhaustion. Nat Immunol. 2022;23(6):848–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Fogel LA, Sun MM, Geurs TL, Carayannopoulos LN, French AR. Markers of nonselective and specific NK cell activation. J Immunol. 2013;190(12):6269–76.

    Article  CAS  PubMed  Google Scholar 

  90. Hu Z, Zhao H-M, Li C-L, Liu X-H, Barkan D, Lowrie DB, et al. The role of KLRG1 in human CD4 + T-Cell immunity against tuberculosis. J Infect Dis. 2018;217(9):1491–503.

    Article  CAS  PubMed  Google Scholar 

  91. McLane LM, Abdel-Hakeem MS, Wherry EJ. CD8 T cell exhaustion during chronic viral infection and Cancer. Annu Rev Immunol. 2019;37:457–95.

    Article  CAS  PubMed  Google Scholar 

  92. Bengsch B, Seigel B, Ruhl M, Timm J, Kuntz M, Blum HE, et al. Coexpression of PD-1, 2B4, CD160 and KLRG1 on exhausted HCV-specific CD8 + T cells is linked to antigen recognition and T cell differentiation. PLoS Pathog. 2010;6(6):e1000947.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Streeck H, Kwon DS, Pyo A, Flanders M, Chevalier MF, Law K, et al. Epithelial adhesion molecules can inhibit HIV-1-specific CD8⁺ T-cell functions. Blood. 2011;117(19):5112–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Wijaya RS, Read SA, Selvamani SP, Schibeci S, Azardaryany MK, Ong A, et al. Hepatitis C Virus (HCV) Eradication with Interferon-Free Direct-acting antiviral-based therapy results in KLRG1 + HCV-Specific memory natural killer cells. J Infect Dis. 2021;223(7):1183–95.

    Article  CAS  PubMed  Google Scholar 

  95. Wang S, Zhang Q, Hui H, Agrawal K, Karris MAY, Rana TM. An atlas of immune cell exhaustion in HIV-infected individuals revealed by single-cell transcriptomics. Emerg Microbes Infect. 2020;9(1):2333–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Robbins SH, Tessmer MS, Mikayama T, Brossay L. Expansion and contraction of the NK cell compartment in response to murine cytomegalovirus infection. J Immunol. 2004;173(1):259–66.

    Article  CAS  PubMed  Google Scholar 

  97. Wijaya RS, Read SA, Schibeci S, Eslam M, Azardaryany MK, El-Khobar K, et al. KLRG1 + natural killer cells exert a novel antifibrotic function in chronic hepatitis B. J Hepatol. 2019;71(2):252–64.

    Article  CAS  PubMed  Google Scholar 

  98. Park JM, Han YM, Oh JY, Lee DY, Choi SH, Hahm KB. Transcriptome profiling implicated in beneficiary actions of kimchi extracts against Helicobacter pylori infection. J Clin Biochem Nutr. 2021;69(2):171–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Cyktor JC, Carruthers B, Stromberg P, Flaño E, Pircher H, Turner J. Killer cell lectin-like receptor G1 deficiency significantly enhances survival after Mycobacterium tuberculosis infection. Infect Immun. 2013;81(4):1090–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Schmid-Hempel P. Parasite immune evasion: a momentous molecular war. Trends Ecol Evol. 2008;23(6):318–26.

    Article  PubMed  Google Scholar 

  101. Loureiro Salgado C, Mendéz Corea AF, Covre LP, De Matos Guedes HL, Falqueto A, Gomes DCO. Ageing impairs protective immunity and promotes susceptibility to murine visceral leishmaniasis. Parasitology. 2022;149(9):1249–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Gazzinelli R, Xu Y, Hieny S, Cheever A, Sher A. Simultaneous depletion of CD4 + and CD8 + T lymphocytes is required to reactivate chronic infection with Toxoplasma Gondii. J Immunol. 1992;149(1):175–80.

    Article  CAS  PubMed  Google Scholar 

  103. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Wu Q, Jiang L, Li SC, He QJ, Yang B, Cao J. Small molecule inhibitors targeting the PD-1/PD-L1 signaling pathway. Acta Pharmacol Sin. 2021;42(1):1–9.

    Article  PubMed  Google Scholar 

  105. Li L, Wan S, Tao K, Wang G, Zhao E. KLRG1 restricts memory T cell antitumor immunity. Oncotarget. 2016;7(38):61670–8.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Zhang Y, Chen Z, Jiang A, Gao G. KLRK1 as a prognostic biomarker for lung adenocarcinoma cancer. Sci Rep. 2022;12(1):1976.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Saleh R, Taha RZ, Toor SM, Sasidharan Nair V, Murshed K, Khawar M, et al. Expression of immune checkpoints and T cell exhaustion markers in early and advanced stages of colorectal cancer. Cancer Immunol Immunother. 2020;69(10):1989–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Yamauchi C, Fujii S, Kimura T, Kuwata T, Wada N, Mukai H, et al. E-cadherin expression on human carcinoma cell affects trastuzumab-mediated antibody-dependent cellular cytotoxicity through killer cell lectin-like receptor G1 on natural killer cells. Int J Cancer. 2011;128(9):2125–37.

    Article  CAS  PubMed  Google Scholar 

  109. Masuda K, Kornberg A, Miller J, Lin S, Suek N, Botella T et al. Multiplexed single-cell analysis reveals prognostic and nonprognostic T cell types in human colorectal cancer. JCI Insight. 2022;7(7).

  110. Paul S, Kulkarni N, Shilpi, Lal G. Intratumoral natural killer cells show reduced effector and cytolytic properties and control the differentiation of effector Th1 cells. Oncoimmunology. 2016;5(12):e1235106.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Herndler-Brandstetter D, Ishigame H, Shinnakasu R, Plajer V, Stecher C, Zhao J, et al. KLRG1(+) Effector CD8(+) T cells lose KLRG1, differentiate into all memory T cell lineages, and convey enhanced protective immunity. Immunity. 2018;48(4):716–e298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. López-Soto A, Gonzalez S, Smyth MJ, Galluzzi L. Control of Metastasis by NK Cells. Cancer Cell. 2017;32(2):135–54.

    Article  PubMed  Google Scholar 

  113. Liu ZG, Jiao D. Necroptosis, tumor necrosis and tumorigenesis. Cell Stress. 2019;4(1):1–8.

    Article  PubMed  PubMed Central  Google Scholar 

  114. Kocak E, Lute K, Chang X, May KF Jr., Exten KR, Zhang H, et al. Combination therapy with anti-CTL antigen-4 and anti-4-1BB antibodies enhances cancer immunity and reduces autoimmunity. Cancer Res. 2006;66(14):7276–84.

    Article  CAS  PubMed  Google Scholar 

  115. Li B, Lin J, Vanroey M, Jure-Kunkel M, Jooss K. Established B16 tumors are rejected following treatment with GM-CSF-secreting tumor cell immunotherapy in combination with anti-4-1BB mAb. Clin Immunol. 2007;125(1):76–87.

    Article  CAS  PubMed  Google Scholar 

  116. Malaisé M, Rovira J, Renner P, Eggenhofer E, Sabet-Baktach M, Lantow M, et al. KLRG1 + NK cells protect T-bet-deficient mice from pulmonary metastatic colorectal carcinoma. J Immunol. 2014;192(4):1954–61.

    Article  PubMed  Google Scholar 

  117. Göthert JR, Eisele L, Klein-Hitpass L, Weber S, Zesewitz ML, Sellmann L, et al. Expanded CD8 + T cells of murine and human CLL are driven into a senescent KLRG1 + effector memory phenotype. Cancer Immunol Immunother. 2013;62(11):1697–709.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Zeng X, Yao D, Liu L, Zhang Y, Lai J, Zhong J, et al. Terminal differentiation of bone marrow NK cells and increased circulation of TIGIT(+) NK cells may be related to poor outcome in acute myeloid leukemia. Asia Pac J Clin Oncol. 2022;18(4):456–64.

    Article  PubMed  Google Scholar 

  119. Noviello M, Manfredi F, Ruggiero E, Perini T, Oliveira G, Cortesi F, et al. Bone marrow central memory and memory stem T-cell exhaustion in AML patients relapsing after HSCT. Nat Commun. 2019;10(1):1065.

    Article  PubMed  PubMed Central  Google Scholar 

  120. Wan Y, Chen M, Li X, Han X, Zhong L, Xiao F, et al. Single-cell RNA sequencing reveals XBP1-SLC38A2 axis as a metabolic regulator in cytotoxic T lymphocytes in multiple myeloma. Cancer Lett. 2023;562:216171.

    Article  CAS  PubMed  Google Scholar 

  121. Wu H, Tang X, Kim HJ, Jalali S, Pritchett JC, Villasboas JC et al. Expression of KLRG1 and CD127 defines distinct CD8(+) subsets that differentially impact patient outcome in follicular lymphoma. J Immunother Cancer. 2021;9(7).

  122. Kobayashi T, Doff BL, Rearden RC, Leggatt GR, Mattarollo SR. NKT cell-targeted vaccination plus anti-4-1BB antibody generates persistent CD8 T cell immunity against B cell lymphoma. Oncoimmunology. 2015;4(3):e990793.

    Article  PubMed  PubMed Central  Google Scholar 

  123. Kerage D, Soon MSF, Doff BL, Kobayashi T, Nissen MD, Lam PY, et al. Therapeutic vaccination with 4-1BB co-stimulation eradicates mouse acute myeloid leukemia. Oncoimmunology. 2018;7(10):e1486952.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Ponzetta A, Benigni G, Antonangeli F, Sciumè G, Sanseviero E, Zingoni A, et al. Multiple myeloma impairs bone marrow localization of Effector Natural Killer cells by altering the Chemokine Microenvironment. Cancer Res. 2015;75(22):4766–77.

    Article  CAS  PubMed  Google Scholar 

  125. Ramello MC, Núñez NG, Tosello Boari J, Bossio SN, Canale FP, Abrate C, et al. Polyfunctional KLRG-1(+)CD57(+) senescent CD4(+) T cells infiltrate tumors and are expanded in peripheral blood from breast Cancer patients. Front Immunol. 2021;12:713132.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Patel SA, Minn AJ. Combination Cancer Therapy with Immune Checkpoint Blockade: mechanisms and strategies. Immunity. 2018;48(3):417–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Scott EN, Gocher AM, Workman CJ, Vignali DAA, Regulatory T, Cells. Barriers of Immune Infiltration into the Tumor Microenvironment. Front Immunol. 2021;12:702726.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Togashi Y, Shitara K, Nishikawa H. Regulatory T cells in cancer immunosuppression - implications for anticancer therapy. Nat Rev Clin Oncol. 2019;16(6):356–71.

    Article  CAS  PubMed  Google Scholar 

  129. Tanaka A, Sakaguchi S. Targeting Treg cells in cancer immunotherapy. Eur J Immunol. 2019;49(8):1140–6.

    Article  CAS  PubMed  Google Scholar 

Download references


We sincerely appreciate the enormous amount of time and effort expended by editorial board and peer reviewers.


This work was supported by grants from the Fundamental Research Funds for the Central Universities (Grant number: 2022CDJYGRH-001) and the Chongqing Medical Scientific Research Project (Joint project of Chongqing Health Commission and Science and Technology Bureau) (Grant number: 2021MSXM272).

Author information

Authors and Affiliations



ZY, YL, SC and YZ constructed and designed the manuscript. YZ and SC wrote the original draft preparation. ZY and YL contributed constructive suggestions. XT, YP, TJ, XZ, and JL reviewed the manuscript. All authors contributed to the article and approved the submitted version.

Corresponding authors

Correspondence to Yao Liu or Zailin Yang.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, Y., Chen, S., Tang, X. et al. The role of KLRG1: a novel biomarker and new therapeutic target. Cell Commun Signal 22, 337 (2024).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: