Differential Sensitivity to IL-12 Drives Sex-Specific Differences in the CD8+ T Cell Response to Infection

It is well known that males and females respond differently to intracellular pathogens. Females mount a more robust immune response than males, which decreases their susceptibility to infection but comes at the cost of increasing immunopathology. However, the underlying basis for sex-specific differences in the CD8(+) T cell response to infection remains poorly understood. In this study, we show that female CD8(+) T cells have an intrinsic propensity to become short-lived effectors, whereas male CD8(+) T cells give rise to more memory precursor effector cells after murine infection with either a virus (vaccinia virus) or bacteria (Listeria monocytogenes). Interestingly, we found that the propensity of female CD8(+) T cells to form short-lived effectors is not because they respond to lower amounts of cognate Ag but rather because they have an enhanced capacity to respond to IL-12, which facilitates more effector cell differentiation at each round of cell division. Our findings provide key insights into the sex-based immunological differences that underlie variations in the susceptibility to infection in males and females. ImmunoHorizons, 2019, 3: 121–132.