A programming role for interleukin-2 in the differentiation of effector and memory CD8+ T cells, unique from IlL-15 and independent of STAT5.

摘要

Environmental signals, including cytokines, received by CD8+ T cells during the primary response to acute infection shape their commitment to effector and memory CD8+ T cell fates, as well as their ability to respond to future pathogen challenges. The common gamma chain (γc) cytokine interleukin-2 (IL-2) provides a memory differentiation signal during the primary response that programs CD8+ T cells for successful recall responses later. We find that although primary effector CTL development is modestly decreased in the absence of IL-2, the persistence of terminal effector phenotype and tissue residing memory CD8+ T cell populations after pathogen clearance is greatly diminished. Furthermore, memory CD8+ T cells generated in the absence of IL-2 signals are unable to undergo secondary effector CTL differentiation. We conclude that IL-2 promotes entry into and survival within an effector CD8+ T cell differentiation program.;The role of IL-2 in promoting primary and secondary effector CTL differentiation is not shared by the highly related cytokine, IL-15. Although IL-15 supports the survival of effector phenotype CD8+ T cells after pathogen clearance, its absence does not impair either primary or secondary effector CTL differentiation, nor does it impact the differentiation of long-term effector memory CD8+ T cells. Thus, there is a unique role for IL-2, but not IL-15, in promoting the differentiation of effector CTL and programming memory CD8+ T cells capable of secondary effector differentiation.;How CD8+ T cells integrate IL-2 signals and the molecular nature of these signals in the development of functional memory populations is not understood. Because IL-2 induces potent activation of the STAT5 transcription factor, we tested the role of STAT5 in CD8+ effector and memory differentiation. We find that STAT5 activity is broadly important for the expansion and effector functions of all effector CTL subsets during the primary response. Despite a broad role in expansion, the requirement for STAT5 was particularly important for survival of terminal effector phenotype and tissue residing memory CD8+ T cells after pathogen clearance. Surprisingly, although STAT5 was important in primary effector CTL responses, and unlike IL-2, STAT5 activity is not required for the development of memory CD8 + T cells capable of robust secondary expansion and secondary effector differentiation upon rechallenge. These findings highlight differential requirements for survival signals between primary and secondary effector CTL, and subsets of memory CD8+ T cells. Furthermore, we demonstrate that IL-2 dependent programming of memory CD8+ T cells capable of protective recall responses is STAT5 independent.