Length of Antigenic Stimulation During Expansion Dictates Commitment to CD8 T Cell Memory Subsets (43.6)

Abstract

Abstract There is considerable interest in understanding early events that drive CD8 T cells towards diverse cell fate decisions: differentiation into central memory (TCM), effector memory (TEM) or terminal effector (TE) subsets. Although, a brief antigenic encounter is sufficient to trigger a cell autonomous program of clonal expansion and differentiation of naïve cells into effector and memory cells, how the ensuing differentiation program is impacted by subsequent antigenic stimulation in the setting of an acute infection is unclear. Here we show that commitment to the TCM, TEM and TE subsets occurs early during the induction and expansion phase of CD8 T cell responses. Repetitive antigen encounters during expansion and the extent of proliferation conditioned by it play a major role in dictating this memory subset commitment, such that increasing antigenic encounter favors TE>>TEM>TCM differentiation. Interestingly, early effectors that preferentially differentiate into TCM, exhibit a novel signature; in addition to elaborating characteristic cytotoxic function, they exhibit strong IL-2 production, a property typically ascribed to naïve and TCM cells. Gene profiling of this novel IL-2+ effector subset revealed that they represent a slightly less differentiated effector subset compared to the non-IL-2 producing counterparts, even though their ex-vivo and in-vivo cytotoxic potential were comparable. These studies underscore the importance of the length of antigenic stimulation, in regulating the commitment to various memory lineages, and will likely provide leads upon which tailored vaccines can be designed. Supported by EGPAIDS Foundation Scholar Awards to SS & VK, & NIH & Gates Foundation Grants to RA