Project Summary

Peripherally induced regulatory T cells (iTreg) is the predominant source of T cell suppressor activity in the human immune system and, as such, the possibility to control their development holds tremendous therapeutic promise. The capacity to modulate the homeostatic equilibrium between peripheral effector function, memory and suppressor Treg will depend on our understanding of the molecular program that governs this process. Our laboratory has generated preliminary evidences suggesting that Polyunsaturated fatty acids (PUFAs) interfere with the generation of iTreg. We postulate that PUFAs control the T cell response through three different but related mechanisms: 1) changing the composition and structure of the cell membrane; 2) regulating signaling networks and gene expression through the synthesis of eicosanoids; and 3) controlling cell fate decisions in different cell activities and developmental processes. The major goal of this project is to define the molecular mechanisms underlying the role of PUFAs in the dynamics of iTreg generation. Specifically, we propose to: 1) test the hypothesis that the lipid architecture of the T cell plasma membrane is altered by PUFA treatment; 2) test the hypothesis that PUFAs regulate the eicosanoid synthesis in T cells; and 3) test the hypothesis that PUFAs control peripheral iTreg development and stability. Molecular, biochemical, and imaging approaches already set up in the laboratory, the scientific environment generated at the Center of Biomedical Research Excellence (COBRE) in the Molecular Basis of Human Disease, and the state-of-the-art facilities of the University of Kentucky School of Medicine will provide a strong foundation for the accomplishment of the scientific goals proposed in this application.

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