Division-linked generation of death-intermediates regulates the numerical stability of memory CD8 T cells

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Abstract
Infection or successful vaccination results in the formation of long-lived memory CD8 T-cell populations. Despite their numerical stability, memory CD8 T-cell populations are thought to completely turn over through proliferation within a 2- to 3-mo period. Therefore, steady-state memory cell proliferation must be balanced by a precisely regulated and equivalent death rate. However, the mechanisms regulating this balancing process remain completely undefined. Herein, we provide evidence for "death-intermediate memory cells" (T(DIM)) within memory CD8 T-cell populations generated by infection. Importantly, CD62L(Lo)/CD27(Lo) T(DIM)s are functionally characterized by an inability to produce cytokines, the failure to internalize T-cell receptor following antigenic stimulation, and signatures of apoptotic death. Furthermore, we demonstrate that, mechanistically, T(DIM) are directly generated from dividing "central memory" T-cell populations undergoing memory turnover in vivo. Collectively, these results demonstrate that as central memory CD8 T cells proliferate, they continuously generate a population of CD8 T cells that are nonfunctional and apoptotic; thus, our data support a model wherein division-linked generation of T(DIM) contributes to numerically stable CD8 T-cell memory.