γ_c deficiency precludes CD8~+ T cell memory despite formation of potent T cell effectors

摘要

Several cytokines (including IL-2, IL-7, IL-15, and IL-21) that signal through receptors sharing the common γ chain (γ_c) are critical for the generation and peripheral homeostasis of naive and memory T cells. Recently, we demonstrated that effector functions fail to develop in CD4~+ T cells that differentiate in the absence of γ_c. To assess the role of γ_c cytokines in cell-fate decisions that condition effector versus memory CD8~+ T cell generation, we compared the response of CD8~+ T cells from γ_c~+ or γ_c~- P14 TCR transgenic mice after challenge with lymphocytic choriomeningitis virus. The intrinsic IL-7-dependent survival defect of γ_c~- naive CD8~+ T cells was corrected by transgenic expression of human Bcl-2. We demonstrated that although yc-dependent 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., KLRG1~(high) CD127~(low) short-lived effector T cells) via the transcription factor, T-bet. Moreover, the γ_c -dependent signals that are critical for memory T cell formation are not rescued by Bcl2 overexpression. Together, these data reveal an unexpected divergence in the requirement for γ_c cytokines in the differentiation of CD4~+ versus CD8~+ cytotoxic T lymphocytes.