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

Abstract

Sex is a significant contributor to the outcome of human infections. Males are frequently more susceptible to viral, bacterial, and fungal infections, which is often attributed to a weaker immune response. 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-specific 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 mice but not in male mice. CVB3 also increased the proportion and number of CD11ahiCD62Llo CD8+ T cells in female mice, indicative of activation. Further, this response was independent of the inoculation route and type I interferon. 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. These data demonstrate that CVB3 induces a sex-dependent CD8+ T cell response and highlight the importance of sex-specific immune responses to viral pathogens.

A viral-specific CD4+T cell response protects female mice from Coxsackievirus B3 infection

“…We previously found that splenic CD4 + and CD8 + T cells expand at 5dpi in orally CVB3-infected female Ifnar -/- mice but not infected male Ifnar -/- mice (30). In contrast to antigen-experienced CD8 + T cells that increase as early as 5 dpi, we found that splenic antigen-experienced CD4 + T cells from female mice do not increase until 15 dpi (30).…”

“…We previously found that splenic CD4 + and CD8 + T cells expand at 5dpi in orally CVB3-infected female Ifnar -/- mice but not infected male Ifnar -/- mice (30). In contrast to antigen-experienced CD8 + T cells that increase as early as 5 dpi, we found that splenic antigen-experienced CD4 + T cells from female mice do not increase until 15 dpi (30). However, we hypothesized that splenic CD4 + T cells may be undergoing signs of early activation even though the upregulation of the cell surface expression of the surrogate makers, CD11a and CD49d, had not occurred.…”

“…We previously found that following oral inoculation, CVB3 induces a sex-dependent expansion of T cells in the spleen (30). However, since CVB3 initiates infection in the intestine, we examined the CD4 + T cell response in the local lymph node following infection.…”

“…The spleen was harvested from infected mice at 15 dpi, and virus-specific CD4 + T cells were analyzed by flow cytometry using an H2-D b GP 66 tetramer. We initially chose to study CD4 + T cells at 15 dpi, based on our previous data measuring the expansion of antigen-experienced CD4 + T cells (30). At 15 dpi, we observed a significant increase in the number of GP 66 -specific CD4 + T cells in the spleen from female mice infected with the rCVB3.6 virus compared to female mice infected with wtCVB3 (Fig.…”

“…In support of this, we recently identified a sex difference in the T cell response to CVB3. We demonstrated that activated, viral-specific CD8 + T cells in female but not male mice expand and protect against CVB3 infection (30). Similarly, we found that CD4 + T cells expand in a sex-dependent manner.…”