Chemokines have been implicated in the control of lymphocyte trafficking and microenvironmental positioning during normal lymphocyte recirculation, and during immune responses. This proposal focuses on understanding the role of the novel chemokine receptor CCR9 and its chemoattractant ligand TECK in the intestinal immunity. The investigator has shown that CCR9 is expressed by a discrete subset of circulating a4J37 + """"""""intestinal"""""""" memory T cells, and by almost all lamina propria and intraepithelial lymphocytes in the small intestines; and that its ligand TECK is preferentially expressed by epithelial cells of the small intestines. Here, the investigator shall explore the hypothesis that this receptor-ligand pair plays a fundamental role in targeting small intestinal immune cells, helping to segregate mucosal from systemic immune response modalities (and potentially even small from large intestinal immune responses). 1) The phenotype and functional properties of CCR9+ lymphocyte subsets in man will be characterized by flow cytometric and cytokine assays; and the involvement of CCR9 and TECK in the chemotactic responses of intestinal vs. systemic lymphocytes in mice will be assessed in transwell chemotaxis assays. 2) The cellular sites of TECK mRNA expression will be defined by in situ hybridization, and the distribution of TECK at the protein level will be explored by immunohistochemistry in intestines and other tissues. 3) The investigator shall determine whether CCR9+ cells comprise circulating memory and/or effector cells for intestinal recall antigens, using the immune response to rotavirus, a well characterized small intestinal pathogen, as a model. In vitro assays of T cell memory responses, antigen-binding assays of B cells, and in vivo assays of immunity in the mouse, will be used to characterize rotavirus-specific B and T lymphocytes and assess their expression of CCR9. 4) Finally, the role of CCR9 and TECK in physiologic lymphocyte trafficking to the intestines will be evaluated by in situ videomicroscopy, focusing on their hypothesized involvement in transendothelial diapedesis. The studies proposed will define critically the importance of CCR9 and its ligand TECK for homing of lymphocytes to the small intestinal lamina propria, their role in segregating intestinal immune responses, and their potential as therapeutic targets in inflammatory bowel diseases.
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