With the proposed Mentored Clinical Scientist Development Award, the applicant will build upon his prior experiences in integrin biology and innate immunity to study lymphocyte trafficking and function in intestinal inflammation and its relevance in mechanisms of inflammatory bowel disease to enhance his skills in mucosal immunology and biology. The laboratory of Andrew D. Luster, MD, PhD, at the Massachusetts General Hospital will provide a rich intellectual environment to foster the candidate's scientific development toward his goal of independent investigation. The proposed study will provide the applicant with the opportunity to study the role of chemokines and chemokine receptors in regulatory T cell trafficking and function in a murine model of inflammatory bowel disease. Activated CD4+ T cells play a pivotal role in pathologic immune response in human inflammatory bowel disease. Murine model of adoptive transfer of CD4+CD45RBhigh T cells without or with co-transfer of CD4+CD25+ regulatory T cells into immunodeficient recipient mice offered a unique opportunity to study the role of regulatory T cells in intestinal mucosa inflammation, and greatly facilitated our understanding of the pathological mechanism of human inflammatory bowel disease. Thus far, little is known about the precise mechanism governing regulatory T cell trafficking in vivo, or even the tissue compartment where the inhibition by regulatory T cells occurs. We hypothesize that chemokine receptors play important role in trafficking and function of regulatory T cells in this murine model of experimental colitis. In these proposed studies using Rag-2-/- as recipient mice, we will 1 ) determine the anatomic locations of regulatory T cells following co-transfer with CD4+CD45RB/high T cells; 2) determine the chemokine receptor profile of regulatory T cells recovered from target organs/tissues following adoptive transfer; and 3) determine the important chemokine receptors in pathogenic and regulatory T cell function and trafficking in vivo using chemokine receptor deficient mice as the donor. Results from these studies may provide novel information about the trafficking patterns of regulatory T cells and the expression and function of chemokine receptors in these cells, which could lead to development of novel therapeutic interventions
| Yuan, Qian; Bromley, Shannon K; Means, Terry K et al. (2007) CCR4-dependent regulatory T cell function in inflammatory bowel disease. J Exp Med 204:1327-34 |
| Yuan, Qian; Campanella, Gabriele S; Colvin, Richard A et al. (2006) Membrane-bound eotaxin-3 mediates eosinophil transepithelial migration in IL-4-stimulated epithelial cells. Eur J Immunol 36:2700-14 |
