Hormonal Regulation of Immune Responses

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The CRTh2-PGD2 pathway mediates many homeostatic aspects of cellular function including chemotaxis, cytokine expression and mucous production. CRTh2 is expressed by a number of cell types, though its regulation has been studied mainly in T lymphocytes. Expression of CRTh2 by CD4+ T lymphocytes is a marker of a fully differentiated Th2 cells producing the characteristic type 2 cytokines that mediate physiologic responses such as immune tolerance during pregnancy, fat biogenesis and tissue repair. My laboratory has been studying CRTh2 and its role in Th2 cell biology since 2005. Using whole genome maps of regulatory elements in human cells, we developed an approach to study the molecular regulation of CRTh2 in a cell type-specific manner. Analysis of these regions show that in T cells CRTh2 may be regulated by the glucocorticoid (GC) cortisol and the sex hormone estrogen. Supporting this, our functional data suggest Th2 cell response to GC is enhanced in the presence of estrogen and may involve induction of reactive oxygen species (ROS). It is our hypothesis that hormones regulate T cell fate and their role in immunity by influencing CRTh2 and Th2 cell function in a sex-specific manner. This study is designed to determine how Th2 cells are regulated by cortisol and whether there are differences based on estrogen exposure and/or biological sex. To do this, we will examine hormonal control of CRTh2 expression and signaling, Th2 cell function, ROS production and cellular metabolism and development of a specialized tissue-residing Th2 subset. We will characterize responses of both female and male Th2 cells, to identify general and sex-specific effects. Using Th2 cells as an experimental paradigm will reveal previously unappreciated physiologic responses contributing to CRTh2-mediated signaling and allow us to study how cellular control of ROS regulates their function. Significance: Our findings will be of broad biologic interest as they will be relevant to the many other cell types and systems expressing CRTh2 and utilizing ROS-mediated signaling for cellular regulation. Our study will be carried out primarily by graduate and undergraduate students and so will also facilitate my goal of training the next generation of scientists and instilling in them the importance of incorporating biological sex when studying immune responses.