Identification of a T-bet^hi 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.