Memory T cells arise after acute infection or vaccination and persist long term to rapidly protect against reinfection. By contrast, chronic infection results in the development of exhausted T (Tex) cells with epigenetic profiles that limit T cell proliferation and differentiation. Tex cells exhibit decreased accessibility of effector gene loci and increased accessibility of loci that encode immune checkpoint molecules (such as Pdcd1 and Lag3) and transcription factors associated with exhaustion (such as Tox and Batf). Given that Tex cells are a diverse collection of distinctive cell types, and previous studies that have characterized Tex cells have been conducted on aggregate populations rather than individual clones, it remains unclear whether there exists a subset of Tex cell clones that can generate functional memory responses.

In a recent preprint (not peer reviewed), Raposo et al. leverage recent advances in single-cell RNA and T cell receptor (TCR) sequencing to identify a subset of T cells with functional memory capabilities that arise after chronic infection with lymphocytic choriomeningitis virus (LCMV). In accordance with the published literature, they validate that most Tex cells have transcriptional and epigenetic profiles previously associated with exhaustion; however, they find that the subset termed chronic central memory T (cTcm) cells have transcriptional and epigenetic similarities to bona fide central memory T (Tcm) cells that are generated in the setting of acute infection. Furthermore, the authors validated that cTcm cells and Tcm cells are functionally similar as adoptive transfer of both populations could protect against LCMV rechallenge in mice that lack endogenous T cells.