Early CD8 T cell proliferative heterogeneity entails diverse memory differentiation programs

Abstract

The lineage of memory cells is a key issue that is much debated. While several lines of evidence support the notion that memory cells are direct descendants of effector cells, data suggesting that memory cells do not pass through a fully differentiated effector phase also exist. Recently a tantalizing notion that divergent memory and effector cell fates are decided after the first cell division has also been presented. Considering the fact that initial antigenic encounter programs CD8 T cells to enter a mode of extensive proliferation, we hypothesized that in the setting of an ongoing acute infection events transpiring beyond the first round of cell division are likely to impact cell fate decisions. In this study we performed a detailed analysis of CD8 T cell differentiation with respect to cell division following activation and also evaluated the memory generation potential of CD8 T cells in early or late rounds of cell division. Our studies demonstrate that as cells continue to proliferate beyond the first round of division, they acquire potent effector functions in a largely homogenous manner. While fraction of effector CD8 T cells in both early late rounds of cell division persisted into memory phase, memory cells derived from effector cells in early rounds of cell division preferentially upregulated L‐selectin and localized in the lymph nodes compared to memory cells derived from effector cells in later rounds of cell division. This also correlated with more robust recall proliferation associated with memory cells derived from effector cells in early rounds of cell division. Collectively, these studies present a model that heterogeneity in initial proliferation, putatively from differential priming events, regulates differentiation of memory cells.