Abstract
A hallmark of chronic infections is the presence of exhausted CD8 Tcells, characterized by a distinct transcriptional program compared with functional effector or memory cells, co-expression of multiple inhibitory receptors, and impaired effector function, mainly driven by recurrent Tcell receptor engagement. In the context of chronic lymphocytic choriomeningitis virus (LCMV) infection in mice, most studies focused on studying splenic virus-specific CD8 Tcells. Here, we provide a detailed characterization of exhausted CD8 Tcells isolated from six different tissues during established LCMV infection, using single-cell RNA sequencing. Our data reveal that exhausted cells are heterogeneous, adopt organ-specific transcriptomic profiles, and can be divided into five main functional subpopulations: advanced exhaustion, effector-like, intermediate, proliferating, or memory-like. Adoptive transfer experiments showed that these phenotypes are plastic, suggesting that the tissue microenvironment has a major impact in shaping the phenotype and function of virus-specific CD8 Tcells during chronic infection.
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