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. The primary function of the C-C chemokine receptor 7 (CCR7) is to regulate chemotaxis of T lymphocytes to and within the lymph nodes. Lymph nodes contain high levels of CCR7 agonists, CCL21 and CCL19. Under normal conditions, CCR7+, na?ve T lymphocytes use CCR7 to migrate to the lymph nodes via a CCL21 gradient. In lymph nodes, na?ve T cells encounter the second CCR7 ligand, CCL19, on CCL19 expressing dendritic cells. Once in contact with the T lymphocyte, the dendritic cells present peptides from pathogens. Na?ve T lymphocytes that fail to identify cognate dendritic cells, exit the lymph nodes and return to the circulation. If dendritic cells expressing the proper MHC/antigen combination are detected, T lymphocyte/dendritic cell conjugates form to initiate an immune response. The role of CCL19 found on the surface of the dendritic cells is still being determined. A better understanding of the regulation of receptors that control T lymphocyte lymph node traffic will provide knowledge to manipulate the movement of T lymphocytes and ultimately the immune response of the host. Several steps in the trafficking of lymphocytes are understood. First, na?ve T lymphocytes use CCR7 to enter lymph nodes via chemotaxis to CCL21. Second, Edg-1 (Endothelial differentiation sphingo-lipid G protein-coupled receptor 1) controls T lymphocyte exit from the lymph nodes via sphingosine 1 phosphate. Third, Kruppel Like Factor 2 (KLF2) induces expression of Edg-1, and fourth the expression of KLF2 is induced by the extracellular regulated kinase 5 (ERK5). The role of ERK5, however, in immune cell function is unknown. Our preliminary data demonstrate that activation of CCR7 by CCL19 but not CCL21 in a human T cell line and in primary T cells induces phosphorylation of ERK5 within one hour and up-regulation of KLF2 within 24 hours. Furthermore, we demonstrate that stimulation of these cells with CCL19, but not with CCL21, over 24-72 hours, leads to increased migration of HuT 78 cells to S1P and expression of Edg1. Taken together, these results suggest that CCR7/CCL19 links lymph node entry of T lymphocytes to the Edg-1 regulated lymph node exit. Our studies this year will focus on how CCL19, but not CCL21 initiate such distinct responses.
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