Homéostasis and differentiation of CD8 T lymphocytes in the absence of common gamma chain-dependent cytokines
Cytokines signalling through receptors sharing the γc chain, especially IL-7, are critical for the development and peripheral homeostasis of naïve T cells. Furthermore, IL-2, -7, -15 and -21 are pleiotropic factors that can play complimentary or overlapping roles in T cell homeostasis and immune responses to infection. However, identification of their precise function during an anti-viral immune response has been challenging. Indeed, γc deficiency affects not only the survival of naïve T cells but also the function of regulatory T cells, limiting the use of γc-deficient mice for assessing T cell immunity. Furthermore, the exact contribution of the γc-dependent cytokines in the differentiation of CD8 T cells remains disputed. Indeed, it is unclear at which step of the differentiation process these cytokines impact and what is their importance on the cellfate decision towards terminal differentiation versus memory generation. In order to assess the impact of γc deficiency on the biology of naïve CD8 T cells, we derived P14 TCR transgenic mice on the recombination-activating gene-2 deficient background with or without γc. In this setting, γc -/- naïve CD8 T cells fail to accumulate in peripheral lymphoid organs and the few remaining cells are characterized by small size, decreased expression of MHC class I proteins and enhanced apoptosis. By overexpressing human Bcl-2, an anti-apoptotic molecule, the number of peripheral naïve CD8 T cells that lack γc could be restored. Nevertheless, as described for naïve CD4 T cells, the presence of Bcl-2 could not correct the size and protein synthesis defect of γcdeficient CD8 T cells. We conclude that γc cytokines provide Bcl-2-dependent as well as Bcl-2-independent signals to maintain the phenotype and homeostasis of the peripheral naïve CD8 T cell pool. In order to dissect the entire CD8 T cell differentiation program in the absence of γc, we compared the response of CD8 T cells from γc +/+ or γc -/- P14 Bcl-2 mice after challenge with lymphocytic choriomeningitis virus. We demonstrated that although γcdependent signals are dispensable for the initial expansion and the acquisition of cytotoxic functions following antigenic stimulation, they condition the terminal proliferation and differentiation of CD8 effector T cells (i.e.: KLRG1high CD127low shortlived effector T cells) via the transcription factor, T-bet. Moreover, the γc-dependent signals that are critical for memory T cell formation are not rescued by Bcl-2 overexpression. Together, our results define the critical stages for γc cytokines in the programming of terminal effector CD8 T cells and in the Bcl-2-independent survival and homeostatic proliferation of memory CD8 T cells.