Sex-specific differences in the CD8+ T cell response to infection is linked to differences in IL-12 sensitivity

Abstract

Abstract It is well known that males and females respond differently to intracellular pathogens. In general, females mount more robust immune responses than males, which decreases susceptibility to infection but comes at the cost of increasing auto-immunopathology. However, the underlying basis for these sex-related differences is poorly understood. In this study, we investigated cell-intrinsic differences between male and female CD8+ T cells. First, we compared the ability of male and female CD8+ T cells to proliferate following in vitro stimulation. Interestingly, we found that female CD8+ T cells proliferate sooner and faster than their male counterparts. Next, we asked whether cell-intrinsic differences between male and female CD8+ T cells contribute to changes in the CD8+ T cell response to infection in vivo. We co-transferred equal numbers of male and female donor CD8+ T cells from TCR transgenic mice into the same host and compared their ability to respond to Listeria monocytogenes. The data indicated that female CD8+ T cells preferentially become short-lived effectors (SLECs), while male donor CD8+ T cells give rise to more memory precursor cells (MPECs), even when placed in the same environment. To gain insight into why female CD8+ T cells are inherently more responsive to infection, we performed a series of in vitro and in vivo experiments, whereby either antigen (signal 1) or IL-12 (signal 3) was titrated. These studies showed that male and female CD8+ T cells respond similarly to low amounts of cognate antigen, but female CD8+ T cells appear to be more sensitive to IL-12. Collectively, our data demonstrates that female CD8+ T cells are biased towards forming SLECs after infection because of their enhanced capacity to respond to IL-12.