Abstract
CD8+ T cell exhaustion limits immune responses during cancer and chronic infection. We identify CD7 as a tissue-specific regulator of terminally exhausted CD8+ T cells during chronic infection. CD7 expression progressively increases during exhaustion, reaching its highest levels on a subset of CD101+Tim3low terminally exhausted cells that arise in the liver. Transcriptomic analysis revealed that CD7-deficient terminally exhausted cells display altered expression of co-stimulatory, translational, and effector genes, correlating with markedly reduced persistence and increased apoptotic susceptibility. Importantly, CD7 is preferentially upregulated on PD-1+CD39+ tumor-infiltrating lymphocytes in human head and neck squamous cell carcinoma, suggesting that CD7 may play a conserved role in promoting exhausted T cell survival. These findings reveal a function for CD7 in sustaining terminally exhausted CD8+ T cells and demonstrate that CD7 signaling is a critical regulator of T cell persistence during chronic infection.