The Role of the Common Cytokine Receptor γ-Chain in Regulating IL-2-Dependent, Activation-Induced CD8+ T Cell Death

Abstract

IL-2-dependent, activation-induced T cell death (AICD) plays an important role in peripheral tolerance. Using CD8+ TCR-transgenic lymphocytes (2C), we investigated the mechanisms by which IL-2 prepares CD8+ T cells for AICD. We found that both Fas and TNFR death pathways mediate the AICD of 2C cells. Neutralizing IL-2, IL-2Rα, or IL-2Rβ inhibited AICD. In contrast, blocking the common cytokine receptor γ-chain (γc) prevented Bcl-2 induction and augmented AICD. IL-2 up-regulated Fas ligand (FasL) and down-regulated γc expression on activated 2C cells in vitro and in vivo. Adult IL-2 gene-knockout mice displayed exaggerated γc expression on their CD8+, but not on their CD4+, T cells. IL-4, IL-7, and IL-15, which do not promote AICD, did not influence FasL or γc expression. These data provide evidence that IL-2 prepares CD8+ T lymphocytes for AICD by at least two mechanisms: 1) by up-regulating a pro-apoptotic molecule, FasL, and 2) by down-regulating a survival molecule, γc.