Coxsackievirus B3 elicits a protective, sex-specific CD8 +T cell response in female mice

Abstract

Abstract Sex is a significant contributor to the outcome of human infections. Males are frequently more susceptible to viral, bacterial, and fungal infections, often attributed to weaker immune responses. In contrast, a heightened immune response in females enables better pathogen elimination but leaves females more predisposed to autoimmune diseases. Unfortunately, the underlying basis for sex-specific immune responses remains poorly understood. Here, we show a sex difference in the CD8 +T cell response to an enteric virus, Coxsackievirus B3 (CVB3). We found that CVB3 induced expansion of CD8 +T cells in female Ifnar −/−mice but not in male Ifnar −/−mice. Using a recombinant CVB3 virus expressing a model CD8 +T cell epitope, we found that the expansion of CD8 +T cells is viral-specific and not due to bystander activation. CVB3 also increased the proportion and number of CD11a hiCD62L loCD8 +T cells in female mice, indicative of T cell activation. However, CD8 +T cell activation is dampened by the primary male sex hormone, testosterone, in male mice. Finally, using antibodies to deplete CD8 +T cells, we found that CD8 +T cells are required to limit CVB3-induced disease in female mice. These data demonstrate that CVB3 induces a sex-dependent CD8 +T cell response that is important for viral clearance in female mice and highlights the importance of sex differences in the immune response to viral pathogens. This work was funded by a K01 DK110216, R03 DK124749, and a Biomedical Research Grant from the Indiana Clinical and Translational Sciences Institute to CMR.