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

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). 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. 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. 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.