Minimal model summarizing the roles of SHP-1 and PAG in negative regulation of T cell response in aging. A) The model proposes that in T cells of young individuals, ligation of the TCR and CD28 leads to activation (TCR/CD28*) and concomitant up-regulation of Lck activity resulting from dephosphorylation of Y505, subsequent release of self-inhibition and activation following autophosphorylation at position Y394. Activation of pLck leads to phosphorylation of ITAM motifs of CD3 and the ζ homodimer, triggering the early events of signal transduction. Data reported here showed that the activity of pSHP-1 in T cells of young subjects was transiently low following T cell activation, whereas pPAG transiently migrated out of lipid rafts. These combined events would favor maintaining upregulation of Lck activity which would fulfill the requirements of Signal 1 of T cell activation. Initiation of the Signal 2 leads to full T cell response. B) A similar series of events occurs in T cells of elderly individuals. However, data reported here showed that the activity of pSHP-1 was sustained in these cells and that pPAG was retained in lipid rafts thus contributing to sustained elevated Csk activity. These combined events would lead to lowered activity of pLck, a decrease of the strength of Signal 1 and, an overall decrease of T cell activation. These conditions lead to a diminished T cell response that contributes to immunosenescence.