Endothelial regulation of IL17 producing T effector cell migration

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DESCRIPTION (provided by applicant): Different subsets of effector T cells contribute in distinct ways to various pathologic conditions. Their migration into tissues is a highly regulated process that involves interactions of the T cells with vascular endothelial cells. My research is currently focused on studying the migratory phenotype of Th17 cells, a newly defined T cell subset that appears to be highly inflammatory and whose mechanisms of migration into inflammatory sites are largely unexplored. My preliminary data indicates that Th17 cells engage in adhesive interactions with selectins, integrins, and endothelium, and show potentially important differences compared to Th1 cells. In this proposal, which includes 3 specific aims, I will further study the interactions of Th17 cells with endothelial cells, with the ultimate goal of determining if Th17 homing into tissues can be specifically targeted in therapeutically useful ways. The techniques which I will have acquired during the mentored phase of the award (defined in aims 1 and 2 of the proposed application) will allow me to develop new technologically advanced methods to further address the role of Th17 cells in inflammation and disease in vivo. This aspect will be pursued during the independent phase of the award (Aim 3). Aim 1 will characterize the adhesion profile of Th17 interactions with endothelial cells and define distinguishing features from Th1. T cell interactions with recombinant adhesion molecules and with activated endothelium under physiological flow conditions in vitro, as well as in vivo, using intravital microscopy (IVM), will be studied. Aim 2 will analyze the expression of ligands for adhesion molecules and chemokine receptors expressed in primary mouse Th17 cells and the cytokine signals that are required for the migratory phenotype observed in Aim 1. Protein and mRNA analysis will be performed. Aim 3 will focus on the migratory behavior of Th17 cells during inflammation in vivo and comparisons will be made with Th1 cells. Distinctly labeled Th17 and Th1 cells will be transferred into different mouse inflammatory models and their migration in the host mice will be analyzed by several quantitative techniques. (End of Abstract)