Latent Plasticity of Effector-like Exhausted CD8 T cells contributes to memory responses

Persistent antigen induces a dysfunctional CD8 T cell state known as T cell “exhaustion” characterized by expression of PD-1 and decreased effector functions 1–3. Nevertheless, dysfunctional CD8 T cells can mediate control of antigen burden which is long-lasting. While significant heterogeneity of exhausted CD8 T cells has been described, the cells which actively proliferate and exert direct viral control have remained elusive. Here, we define subsets of PD-1+ CD8 T cells marked by expression of CX3CR1 exhibit substantial in situ proliferation and expression of granzyme B during chronic infection for the maintenance of the effector pool through self-renewal independently of previously defined stem-like cells. Unexpectedly, the CX3CR1+ CD8 T cells retain plasticity to be reprogrammed to memory cells through expression of TCF-1 and re-gain polyfunctionality. Thus, we define a subset of effector-like exhausted CD8 T cells with capacity to contribute to the memory pool, offering a prime target for novel immunotherapies.