MECHANISMS OF PERIPHERAL REGULATORY T CELL GENERATION

University Of Kentucky, Lexington KY

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Peripherally induced Regulatory T cell (iTregs) is the predominant source of T cell suppressor activity in the human immune system. As such, the possibility to control their development holds a tremendous therapeutic promise. Our lab has established a cell culture system that recapitulates the generation of functional iTregs ex vivo from primary human. Our long term goal is to identify the molecular mechanisms that control T cell activation as a prerequisite to develop therapeutic approaches to induce, direct or restore the normal immunological activity. In recent years, epidemiological and clinical studies have demonstrated the beneficial effects of a balanced consumption of dietary Polyunsaturated Fatty Acids (PUFAs). Currently, the mechanisms underlying PUFA regulation of immune response are largely unknown. We postulate that PUFAs play a crucial role in controlling 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. In this project we will take advantage of a primary human cell culture system to elucidate the role of PUFA in the molecular regulation of T cell activity, with special focus on the dynamic process to generate iTregs. To do so, our experimental research plan will address these three Specific Aims: 1) Test the hypothesis that the lipid architecture of the T cell plasma membrane is altered by PUFA treatment. We will integrate analyses of lipid rafts, protein microclusters and the immune synapse (IS) formation to convey a model of T cell membrane structure, function and dynamics modulated by PUFA. 2) Test the hypothesis that PUFAs regulate the eicosanoid synthesis in T cells. We will analyze and compare the eicosanoid pathways engaged in T cells treated with PUFAs and their potential role in the regulation of gene expression induced by the nuclear receptor Peroxisome Proliferator Activator Receptor gamma (PPAR[unreadable]). 3) Test the hypothesis that PUFAs control peripheral iTreg development and stability. We will analyze and compare the time-course effects of PUFAs on the generation and the stability of iTregs. The results ought to provide a solid foundation to support the development of rational strategies to induce, direct or restore the normal immunological activity in different pathologies, such as autoimmunity, chronic inflammation or cancer. This project has clear and direct relevance to human health since the capacity to modulate the development and/or response of Tregs may become instrumental in controlling the dynamic plasticity of the immune response.