Different subsets of effector T ceils 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. IL-17 producing T helper cells (Th17), a newly defined T cell subset that is pro-inflammatory, can contribute to the inflammatory pathology of organ specific autoimmune diseases, as well as to protective responses against certain microbial infections. The overall aim of this project is to study the regulation of migration of Th17 cells into inflammatory sites with the goal of determining if their homing into tissues can be specifically targeted in therapeutically useful ways. Based on data generated during the K99 funding period, my working hypothesis is that Th17 cells have a different migratory phenotype than Th1 cells, a T cell type that also promotes inflammation. I have established several new in vitro and in vivo assays that will be used to address my specific aims during the ROO phase of this award.
In Aims 1 and 2, the major findings were that (i) Th17 show more robust surface expression of E-selectin ligands including glycoCD43 and as a result adhere more to E-selectin than P-selectin;(ii) that Th17 cells express high levels of the chemokine receptor 6 (CCR6) and readily increase their adhesion to ICAM-1 and TNF-activated endothelial monolayers in the presence ofthe CCR6 ligand, CCL20 under physiological shear flow conditions. Thus Th17 rolling and chemokine activated arrest are important steps during the recruitment to tissues and my findings open a window to explore the existence of as yet unidentified E-Selectin ligands that may be exclusively expressed on Th17 cells. This goal is now incorporated into revised Aims 1 and 2. Similar to what I have done during the K99 award, Aim 3 will interplay with Aims 1 and 2 and will explore using in vivo techniques the relevance of this as yet undefined E-selectin ligand during Th17 cell recruitment in models of inflammation.
Inflammation is a key pathophysiological process in a large number of common diseases and there is evidence from several studies that Thi7 are major contributors to many of these diseases previously believed to be mediated by Thi cells. It is important to define mechanisms of Thi7 mediated migration because current approaches to treat immunologic diseases by migratory blockade were developed before knowledge of Thi 7 cells emerged, and those methods may not target Thi 7 cells.
|Bene, Nicholas C; Alcaide, Pilar; Wortis, Henry H et al. (2014) Mineralocorticoid receptors in immune cells: emerging role in cardiovascular disease. Steroids 91:38-45|
|Alcaide, Pilar; Maganto-Garcia, Elena; Newton, Gail et al. (2012) Difference in Th1 and Th17 lymphocyte adhesion to endothelium. J Immunol 188:1421-30|