Biological Sex As a Critical Variable in CD4⁺Effector T Cell Function in Preclinical Models of Multiple Sclerosis

Abstract

Significance: T cells play a pivotal role in maintaining adaptive immune responses against pathogens. However, misdirected T cell responses against self-tissues may lead to autoimmune disease. Biological sex has profound effects on T cell function and is an important determinant of disease incidence and severity in autoimmune diseases such as multiple sclerosis (MS). Recent Advances: Many autoimmune diseases skew toward higher female incidence, including MS; however, it is has become increasingly more accepted that men living with MS are more prone to developing a progressive disease course and to having worsened disease outcomes. Critical Issues: In this review, we discuss what is known about the role of biological sex on T cell development and differentiation, examining evidence that male sex can augment T helper 17 (Th17) responses. Next, we outline what is known about sex differences in animal models of MS, and about the distinct roles played by sex hormones versus sex chromosomes in pathogenesis in these models. Finally, we discuss recent advances that examine the molecular basis for worsened disease outcomes in males, with a particular focus on the role played by Th17 cells in these models. Future Directions: Better understanding the role of biological sex in T cell function may pave the way to effective personalized treatment strategies in MS and other autoimmune diseases. Antioxid. Redox Signal. 37, 135–149.

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

“…The molecular mechanism for how CD4 + T cells protect against CVB3 is unclear, but sex contributes to CD4 + T cell effector function during different diseases and viral infections ( 18 , 20 , 21 , 50 – 53 ). CD4 + T cells differentiate into multiple effector functions, including Th1, Th2, Treg, and Tfh cell types, which impact viral infections.…”

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

“…These data provide evidence that activation and expansion of CD4 + T cells play a crucial role in limiting CVB3 pathogenesis and further demonstrate the importance that sex plays in immune protection against pathogens. The molecular mechanism for how CD4 + T cells protect against CVB3 is unclear, but sex contributes to CD4 + T cell effector function during different diseases and viral infections (18, 20, 21, 49-52). CD4 + T cells differentiate into multiple effector functions, including Th1, Th2, Treg, and Tfh cell types, which impact viral infections.…”

“…The molecular mechanism for how CD4 + T cells protect against CVB3 is unclear, but sex contributes to CD4 + T cell effector function during different diseases and viral infections (18,20,21,(49)(50)(51)(52). CD4 + T cells differentiate into multiple effector functions, including Th1, Th2, Treg, and Tfh cell types, which impact viral infections.…”

Sex, aging and immunity in multiple sclerosis and experimental autoimmune encephalomyelitis: An intriguing interaction

“…Sex-specific aspects of the immune system: Lessons from EAE There is accumulating evidence that males and females exhibit different immunological responses throughout life, whereas others are only present after puberty and before reproductive senescence, suggesting that both genes and hormones are involved. EAE can be a useful tool to unravel those sex-specific differences in immune responses (58). Notably, different strains display different susceptibility to EAE.…”