Identification of a T-bethi Quiescent Exhausted CD8 T Cell Subpopulation That Can Differentiate into TIM3+CX3CR1+ Effectors and Memory-like Cells

Persistent Ag induces a dysfunctional CD8 T cell state known as "exhaustion" characterized by PD-1 expression. Nevertheless, exhausted CD8 T cells retain functionality through continued differentiation of progenitor into effector cells. However, it remains ill-defined how CD8 T cell effector responses are sustained in situ. In this study, we show using the mouse chronic lymphocytic choriomeningitis virus infection model that CX3CR1(+) CD8 T cells contain a T-bet-dependent TIM3-PD-1(lo) subpopulation that is distinct from the TIM3+CX3CR1(+)PD-1(+) proliferative effector subset. The TIM3-CX3CR1(+) cells are quiescent and express a low but significant level of the transcription factor TCF-1, demonstrating similarity to TCF-1(hi) progenitor CD8 T cells. Furthermore, following the resolution of lymphocytic choriomeningitis virus viremia, a substantial proportion of TCF-1(+) memory-like CD8 T cells show evidence of CX3CR1 expression during the chronic phase of the infection. Our results suggest a subset of the CX3CR1(+) exhausted population demonstrates progenitor-like features that support the generation of the CX3CR1(+) effector pool from the TCF-1(hi) progenitors and contribute to the memory-like pool following the resolution of viremia.