CD1 autoreactive T cells in human inflammatory skin disease

PROJECT SUMMARY CD1 autoreactive T cells in human immune mediated skin disease D. Branch Moody, PI Human skin contains over ten billion resident T cells that participate in host defense, barrier function and autoimmune skin disease. For decades, research into T cell autoreactivity has emphasized T cell receptor (TCR) recognition of MHC-peptide complexes. This R01 program proposes basic research into a different mechanism involving TCR contact with human CD1a proteins expressed on Langerhans cells and lipid antigens. Building on prior studies that discovered lipid antigens and showed the molecular basis for their display by CD1a, we recently discovered an unexpected model whereby T cell receptors directly contact CD1a, and certain endogenous lipids bound to CD1a inhibit TCR contact. The new mechanism of negative regulation expands the scope of CD1a function on Langerhans cells and has potentially broad implications for the control of CD1a autoreactive Th22 T cells in human skin. Using collagen matrices and CD1a tetramers to isolate pure CD1a autoreactive T cells, we will determine T cell receptor patterns, effector functions and the identities of antagonist and agonist lipids in disease settings. We will determine the natural functions of lipid blockers by measuring their production in healthy and diseased skin, as well as in Langerhans cells and related cell types. We will determine the therapeutic potential of lipid blockers by synthesizing analogs to optimize their T cell inhibitory properties. Since we now know that contact allergens can function as CD1a presented antigens, we will test a new model of contact hypersensitivity that involves direct recognition of allergens by lipid specific T cells. Further, we will test the ability of CD1a blockers to prevent T cell response in vivo in CD1a transgenic mice and in human skin explants. In contrast to the ~ 5000 MHC I and II allomorphs present in humans, nearly all humans express the same kind of CD1a proteins. This simplified and relatively uniform T cell system suggests that lipid antigens, lipid antagonists and T cell receptor patterns discovered here will be applicable to all people and can therefore be used to develop therapies against autoimmune skin diseases.