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Gadd45β-induced prolonged activation of p38 kinase defines a novel pathway mediating negative selection of thymocytes

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The clonal deletion of thymocytes by negative selection is an important process to ensure immunologic tolerance, even though the underlying molecular mechanisms are poorly understood. Here, we show that Gadd45β, a regulator of mitogen-activated protein kinases, is critically involved in triggering negative selection. Gadd45β expression was inducible in different models of negative selection. Strikingly, only TCR-ligating peptides resulting in negative selection, but not positively selecting ligands or dexamethasone, a TCR-independent apoptosis agonist, induced Gadd45β expression. Expression of Gadd45β maintained a sustained activation of p38 kinase and thereby promoted TCR-mediated apoptosis. In contrast, inhibition of Gadd45β expression or p38 activity impaired cell death. Moreover, thymocytes from Gadd45β-deficient mice revealed only transient p38 activation, reduced caspase activation and cell death. Thus, we provide evidence that Gadd45β and a resulting persistent activation of p38 constitute a novel apoptotic pathway involved in negative selection.

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Correspondence to E Keil.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Keil, E., Ueffing, N., Liebermann, D. et al. Gadd45β-induced prolonged activation of p38 kinase defines a novel pathway mediating negative selection of thymocytes. Cell Commun Signal 7, A61 (2009) doi:10.1186/1478-811X-7-S1-A61

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Keywords

  • Protein Kinase
  • Dexamethasone
  • Caspase Activation
  • Apoptotic Pathway
  • Negative Selection