Different T cell subsets are defined on the basis of the cytokines they produce, and they perform distinct protective and pathologic roles. Migration of effector T lymphocytes into tissues is regulated by molecular interactions of the T cells with vascular endothelial cells (EC). The chemokine receptors and adhesion molecules characteristic of each T cell subset play essential roles in determining how that subset migrates into tissues and contributes to disease. Thi and Th2 helper T cell subsets, discovered over 20 years ago, secrete interferon y or IL-4, IL-5 and IL-13, respectively. Recently, a third major helper T cell subset called Th17 has been identified. Th17 cells secrete IL-17 and IL-22, and contribute in significant ways to the pathology of organ specific autoimmune diseases, as well as to protective responses against certain microbial infections. There is substantial evidence that CDS"^ T cells can differentiate into IL-17 producing (Tc17) cells as well. The mechanisms of migration of IL-17 producing CD4* and CD8+ (Type 17) T cells into inflammatory sites are largely unexplored relative to interferon-y producing Thi and Tc1 (Type 1) T cells. Our preliminary data indicate that Th17 cells engage in adhesive interactions with selectins, integrins, and EC, and that there are significant differences in the migratory phenotypes of Type 17 and Type 1 cells. In this proposal, we will study EC interactions and migration of Type 17 T cells. The experimental program includes three Specific Aims.
In Aim 1, we will determine the distinguishing features of Type 17 vs. Type 1 interactions with EC, which contribute to temporal or spatial subset specific recruitment and to the association of neutrophilic inflammation with Thi7 cells. We hypothesize that recruitment of one subset will impact on the selectivity of subsequent T cell recruitment. We will also explore if Type 17, but not Type 1 effector T cell recruitment is coordinately regulated with neutrophilic infiltration. The experimental approach will include analyses of protein and mRNA expression of relevant molecules in primary mouse Thi7 and Tcl7 cells and studies of T cell interactions with recombinant adhesion molecules and with endothelium in vitro under physiological flow conditions.
Aim 2 will focus on the molecular signals needed for the acquisition of the selectin-binding phenotype of Type 17 cells, and comparisons will be made with the different signals required selectin ligand expression in Type 1 T cells. The experimental approach will involve analysis of different cytokine signals and downstream transcription factors linked to expression of selectin ligands, with a particular focus on the contrasting roles of RORyT and Tbet, which are the signature transcriptional regulators of Th17 and Th1 cells.
Aim 3 will compare the recruitment of Type 17 and Type 1 effector T cells in vivo. The experimental approach will include transfer of distinctly labeled Thi7, Tcl7, Th1 and Tc1 populations into different mouse inflammatory models. The migratory behavior of the Type 17 and Type 1 T cells in the host mice will be assessed by several quantitative techniques. The adhesion pathways and chemokines identified in Aim 1 will be evaluated in these models using antibody blocking and T cells or host mice genetically deficient in adhesion molecules and chemokine receptors. Collaborative studies with Projects 1 and 3 will focus on CD47- and integrin-dependent mechanisms of Th17- and Tc17-endothelial interactions. The information obtained from these studies will be essential for a full understanding the important recruitment phase of T cell-mediated diseases, and the data will help determine therapeutic targets that are T cell subset specific.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Brigham and Women's Hospital
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Brown, Jonathan D; Lin, Charles Y; Duan, Qiong et al. (2014) NF-?B directs dynamic super enhancer formation in inflammation and atherogenesis. Mol Cell 56:219-31
Luscinskas, Francis W; Imhof, Beat A (2014) Introduction for the special issue on new paradigms in leukocyte trafficking, lessons for therapeutics. Semin Immunopathol 36:133-6
Leick, Marion; Azcutia, Veronica; Newton, Gail et al. (2014) Leukocyte recruitment in inflammation: basic concepts and new mechanistic insights based on new models and microscopic imaging technologies. Cell Tissue Res 355:647-56
Massaad, Michel J; Oyoshi, Michiko K; Kane, Jennifer et al. (2014) Binding of WIP to actin is essential for T cell actin cytoskeleton integrity and tissue homing. Mol Cell Biol 34:4343-54
Mayadas, Tanya N; Cullere, Xavier; Lowell, Clifford A (2014) The multifaceted functions of neutrophils. Annu Rev Pathol 9:181-218
Venkatesh, Deepak; Ernandez, Thomas; Rosetti, Florencia et al. (2013) Endothelial TNF receptor 2 induces IRF1 transcription factor-dependent interferon-? autocrine signaling to promote monocyte recruitment. Immunity 38:1025-37
Azcutia, Veronica; Routledge, Matthew; Williams, Marcie R et al. (2013) CD47 plays a critical role in T-cell recruitment by regulation of LFA-1 and VLA-4 integrin adhesive functions. Mol Biol Cell 24:3358-68
Griffin, Gabriel K; Lichtman, Andrew H (2013) Two sides to every proinflammatory coin: new insights into the role of dendritic cells in the regulation of T-cell driven autoimmune myocarditis. Circulation 127:2257-60
Martinelli, Roberta; Newton, Gail; Carman, Christopher V et al. (2013) Novel role of CD47 in rat microvascular endothelium: signaling and regulation of T-cell transendothelial migration. Arterioscler Thromb Vasc Biol 33:2566-76
Alcaide, Pilar; Maganto-Garcia, Elena; Newton, Gail et al. (2012) Difference in Th1 and Th17 lymphocyte adhesion to endothelium. J Immunol 188:1421-30

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