Early sex-related transcriptional differences in CD8+ T cells responding to chronic viral infection reveal a sex bias in exhaustion development

CD8+ T cell diversity is essential to control infections and chronic antigen stimulation. In acute-resolving infection, effector cells mediate acute responses and memory cells provide long-lived protection against future exposures. In chronic infection and cancer, an altered state called exhaustion occurs. Exhausted CD8+ T cells are molecularly and functionally distinct from effector and memory cells. Differences in immune responses exist between biological sexes, however, how biological sex influences the timing and transcriptional programs of CD8+ T cell responses during chronic versus acute viral infection remains unknown. Here, we show that male and female CD8+ T cells exhibit transcriptional differences in their early responses during chronic but not acute viral infection in vivo. Using single-cell RNA-sequencing analyses, we show that female CD8+ T cells adopt an early exhaustion-like program compared to males. Moreover, we found sex-related differences in single-cell gene expression dynamics and fundamental cellular processes early after chronic infection. These findings reveal new insights into sex-related differences in CD8+ T cell exhaustion development and early T cell responses that may contribute to sex differential immune responses.