Role of Retinoic Acid in Regulation of Intestinal T cells
Abstract
Epidemiological studies have shown that vitamin A is essential micronutrient for proper immune function. However, the detailed mechanisms by which vitamin A and its active metabolite retinoic acid (RA) regulate the immune cells are largely unknown. We investigated the novel regulatory role of RA in the intestinal immune system. RA has been known to regulate CD4+ T cell migration and differentiation. We discovered that RA also regulates T cell survival by induction of an apoptosis-inducing purinergic receptor P2X7. RA induces P2X7 expression by direct binding to the intragenic enhancer of P2X7 gene in CD4+ T cells, rendering them highly susceptible to P2X7-mediated cell death which is triggered by extracellular ATP and NAD. This tolerogenic mechanism was shown to be especially important in the intestine where RA concentration and extracellular ATP/NAD concentrations were believed to be high, by demonstrating aberrant expansion of Th1/Th17 cells in the intestine of P2X7-null mice as well as amelioration of CD4+ T cell-induced-colitis with administration of NAD. We concluded that this RA-P2X7 axis is a novel immune homeostatic mechanism by which over-population of effector T cells is prevented. As illustrated well in this study, effects of RA is cell type-specific and pleiotropic. It is important to recognize that cell- and microenvironment-specific factors cooperate with RA to produce certain physiological outcomes as exemplified in part I of our study which show that RA, P2X7, and extracellular NAD work together to induce apoptosis of T cells. In addition, detailed immune phenotyping is necessary to better understand the roles of RA in a certain immunological context. Our study provided novel information to the existing knowledge regarding the complex roles of RA in the immune system. Uncovering the intricate relationship between this micronutrient and immune system will likely produce more exciting findings in the future.
Degree
Ph.D.
Advisors
Kim, Purdue University.
Subject Area
Immunology
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