Daniel, Yost, and Hsiung et al. generated a differentiation atlas of T cell exhaustion in murine chronic viral infection. Analysis revealed that a Tex program is likely initiated in an early effector exhausted (Texeeff) subset, which differentiates towards a progenitor subset (Texprog), followed by an intermediate (Texint) subset. Differentiation then bifurcates towards a late-stage terminal exhaustion (Texterm) phenotype associated with high TCR avidity, a killer cell lectin-like receptor-expressing cytotoxic (TexKLR) phenotype associated with low TCR avidity, or “divergent” clones that acquire both phenotypes. Trajectories were generally shared across tissues. Similar patterns could be observed in human TILs.
Contributed by Lauren Hitchings
ABSTRACT: Chronic antigen exposure during viral infection or cancer promotes an exhausted T cell (Tex) state with reduced effector function. However, whether all antigen-specific T cell clones follow the same Tex differentiation trajectory remains unclear. Here, we generate a single-cell multiomic atlas of T cell exhaustion in murine chronic viral infection that redefines Tex phenotypic diversity, including two late-stage Tex subsets with either a terminal exhaustion (Tex(term)) or a killer cell lectin-like receptor-expressing cytotoxic (Tex(KLR)) phenotype. We use paired single-cell RNA and T cell receptor sequencing to uncover clonal differentiation trajectories of Tex(term)-biased, Tex(KLR)-biased or divergent clones that acquire both phenotypes. We show that high T cell receptor signaling avidity correlates with Tex(term), whereas low avidity correlates with effector-like Tex(KLR) fate. Finally, we identify similar clonal differentiation trajectories in human tumor-infiltrating lymphocytes. These findings reveal clonal heterogeneity in the T cell response to chronic antigen that influences Tex fates and persistence.