An Inconvenient Variable: Sex Hormones and Their Impact on T Cell Responses

Abstract

Epidemiologic data demonstrate sex differences in autoimmune diseases, immune responses against infection, and antitumor immunity, and accumulating evidence suggests a major role for sex hormones in mediating these differences. In this study, we review recent advances in understanding how sex hormones regulate T cell responses to alter susceptibility to autoimmunity. Although sex hormones can directly alter gene transcriptional programs of T cells, we focus in this study on how sex hormones alter T cell development and function through their effects on thymic stromal cells and innate cell types. In addition to contributing to our understanding of sex differences, these findings also have implications for the therapeutic use of sex hormones and sex hormone modulators, which are now being prescribed to increasing numbers of patients for a wide variety of indications.

Figure 1.

Sex hormone effects on thymus cell types. Sex hormones induce apoptosis of double positive (DP) progenitors. Additionally, sex hormones directly modulate gene expression in thymic epithelial cells. Androgens downregulate Dll expression in cortical thymic epithelial cells (cTECs) to inhibit thymopoiesis while upregulating Aire in mTECs to promote negative selection of self-reactive T cells. Estrogen downregulates Aire in mTEC to inhibit thymocyte negative selection.

Figure 2.

Proposed regulation of peripheral T cell responses by androgens. Under conditions of relatively high testosterone in males, this hormone acts directly to induce IL-33 expression by mast cells. IL-33 activates the preferential expansion of IL-13-producing ILC2s. IL-13 in turn drives Th2 cell differentiation. Normal adult females express testosterone, but at levels 7-8 times lower than adult males. This reduced level is below the threshold to trigger a strong IL-33 response. Exposure to high testosterone during cell development may alter the Il33 locus increasing chromatin accessibility and expression potential in males. Testosterone promotes Treg cell expansion and function: Indirectly, through induction of IL-33, an ST2+ subset of Treg cells undergo differentiation and local accumulation in tissues. Testosterone may also nfluence acquisition of chromatin modifications in the Foxp3 gene that promote increased Foxp3 expression.