Diet affects both innate and adaptive immune function and thus can influence resistance to and recovery from infectious and inflammatory diseases. Our long-term objective is to define how vitamin A regulates T-cell mediated immune responses. Vitamin A deficiency increases mortality from common childhood infections and impairs immune responses promoted by T-helper type 2 (Th2) cells. These responses include the serum IgG1 and IgE responses, the secretory IgA response, and eosinophil-mediated inflammatory responses, such as occur during gut helminth infections and allergic responses, including asthma. The molecular mechanisms by which vitamin A modulates Th2 responses are not known. We have recently found that stimulation of the retinoid X receptor (RXR) pathway in antigen-naive Th0 cells promotes development of Th2 memory cells (as indicated by the production of IL-4), while stimulation of the retinoic acid receptor (RAR) pathway does not. We propose that RXR-mediated transcription from specific genes is required for normal Th2 development. In this application we propose to identify these genes - using in vitro studies - and determine if RXR is acting alone or together with a partner receptor. The mechanism(s) by which RXR or partner receptor ligands regulate expression (i.e., by interacting with DNA response elements or other protein components of the transcription complex) will be identified. We will then use receptor-selective retinoids and RXR-knockout mice to determine, in vivo, if RXR regulates Th2 cell development and Th2-mediated antibody responses. Identifying the mechanisms by which vitamin A modulates Th2-mediated immune and inflammatory responses will be useful in several ways. It will help in evaluating clinical and public health interventions using vitamin A (and, perhaps, nutrients that bind to RXR partner receptors, such as vitamin D and fatty acids) to decrease morbidity and mortality in deficient populations. Understanding these same mechanisms will also help us determine safe upper limits for nutrient intake in the U.S. population, where chronic inflammatory conditions (mediated by both Th2 and Th1 cells) are highly prevalent. Finally, this work may suggest novel intervention strategies to modulate chronic inflammatory conditions. In addition, receptor-selective retinoids are currently used in cancer therapy and are being evaluated for diabetes. This work will help evaluate possible side effects of these therapies.
