TEXAS A & M RESEARCH FOUNDATION
Many epidemiological and clinical studies have demonstrated that n-3 polyunsaturated fatty acids (PUPA), a bioactive food component, ameliorate immune-mediated inflammatory diseases. A primary effector molecule is thought to be docosahexaenoic acid (DHA, 22:6n-3). However, the precise mechanisms by which DHA influences the maintenance of appropriate T-cell subset balance for a healthy immune system have not been elucidated. Therefore, the overall goal of this proposal is to understand, at a mechanistic level, how dietary DHA modulates T-cell activation and signaling. Our overall hypothesis is that DHA disrupts plasma membrane lipid raft microdomain composition, thereby altering the dynamic partitioning of signaling proteins required for cell proliferation and apoptosis in T-cells. This would selectively alter T-cell receptor (TCR) macromolecular complex signaling, inhibiting activation and cytokine production by T-helper 1 (Th1) cells and/or create a permissive environment for apoptosis in Th1 cells. We will also test the alternative hypothesis that DHA selectively inhibits signaling protein (Lck, Fyn, and LAT) post-translational lipidation, which subsequently may alter lipid raft targeting and protein function. We propose to utilize conventional C57BL/6, IL-10 null, DO11.10-RAG null, and Fat-1 transgenic mouse models to further elucidate the mechanisms by which DHA suppresses Th1-mediated immune responses. The proposed experiments will further elucidate the mechanisms by which DHA: 1) Differentially modulates membrane properties and TCR-dependent signaling in nonpolarized vs Th1 polarized cells; 2) Alters the plasma membrane microenvironment and modulates the function of the major co-regulatory signaling molecules which regulates T-cell proliferation and apoptosis; 3) Directly affects antigen-induced CD4+ T-cell activation and indirectly affects the co-stimulatory environment in vivo; and 4) Suppresses the development of Th1-mediated inflammatory bowel disease in a murine model. Findings from the proposed studies could lead to the development of new therapeutic tools to treat T-cell-mediated inflammation and autoimmunity.