Compelling evidence supports the hypothesis that inflammation contributes significantly to the development of atherosclerotic lesions and to the catastrophic clinical events associated with unstable lesions. Ample evidence from both human and mouse studies indicate that T lymphocytes play important roles in driving inflammation in atherosclerotic disease. Studies from our laboratory have shown that physiologic mechanisms of regulation of T cell immunity, including modulation of helper T cell subset differentiation, co-stimulatory/co-inhibitory pathways, and regulatory T cells, all significantly impact pro-atherogenic T cell responses. Furthermore, we have established that statins suppress inflammatory effector T cell responses through up-regulation of the transcription factor KLF2. These finding serve as the basis for the proposed project, with the broad objective of discovering ways to therapeutically alter or block the pathogenic T cell responses in arteries. This objective will be pursued through experiments with both mouse and human dendritic cells, macrophages and T cells, both in vitro and in vivo. The work will be organized into the following three interrelated Specific Aims: 1- Develop methods of tolerizing proatherogenic T cells based on induction of KLF2 in dendritic cells. 2- Develop approaches to sustain regulatory T cell (Treg) responses in atherosclerotic lesions under conditions of prolonged hypercholesterolemia. 3- Determine the cellular basis of PD-1 mediated suppression of proatherogenic immune responses. Several experimental approaches will be taken including: pharmacologic manipulation and adoptive transfer of dendritic cells between atherosclerotic-prone mouse strains;lineage specific cre-lox mediated deletion of regulatory genes including KLF2 in DCs and PD-1 in T cells and myeloid cells, all in atherosclerotic-prone mince;and analyses of the effects of cholesterol-induced innate inflammation on Treg viability and phenotype. The work proposed in each Aim address a different basic mechanism of the regulation of T cells in atherosclerotic disease that we know is relevant from our previous work. Each of these mechanisms will likely impact the others, and we will study these interactions. Overall, the information obtained will be of direct translational relevance to the development of immunotherapeutic approaches for cardiovascular disease.
Atherosclerosis, a leading cause of morbidity and mortality worldwide, is a chronic inflammatory disease of the arterial wall driven in part by T lymphocyte responses. This project will characterize how proatherogenic T lymphocytes are regulated through the interaction with other cells. If successful, the data generated will help in development of new anti-inflammatory treatments for atherosclerosis.
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