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

Abstract

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.

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

“…Interestingly, IL-12 has also been shown to play a role in a sex-specific T cell response to Listeria monocytogenes . In response to bacterial infection, an enhanced capacity for female CD8 + T cells to respond to IL-12 led to a higher proportion of short-lived effector CD8 + T cells (53). In contrast, L. monocytogenes infection drove male CD8 + T cells toward memory precursor effector cells.…”

Considering how biological sex impacts immune responses and COVID-19 outcomes

“…As vaccines are developed, the female bias towards both potent responses and adverse effects should be considered and sex-specific dosing should be tested, where appropriate 87 . Sex impacts the development of regulatory T cells [88][89][90][91] , the distribution of lymphocyte subsets 92 and the overall quality of T cell responses 93,94 . In T cells, overexpression of X-encoded immune genes, including CD40LG and CXCR3, has been linked to incomplete X chromosome inactivation and T cell-specific epigenetic modifications of the X chromosome 95,96 .…”

The immune response to COVID‐19: Does sex matter?

“…Regulatory T‐cell (Treg) development, 80 , 81 , 82 , 83 lymphocyte subset distribution, 84 and quality of T‐cell responses are all affected by sex. 85 , 86 Higher oestradiol levels increase Tregs, 87 and women have a higher ratio of CD4/CD8 T cells. 88 Researchers did not identify a connection between T‐cell responses and human outcomes in the SARS outbreak.…”

“…Similar to that of humoral responses, the role of sex‐based differences in T‐cell responses in COVID‐19 has also been emerging. Regulatory T‐cell (Treg) development, 80–83 lymphocyte subset distribution, 84 and quality of T‐cell responses are all affected by sex 85,86 . Higher oestradiol levels increase Tregs, 87 and women have a higher ratio of CD4/CD8 T cells 88 .…”