A research career development plan is proposed encompassing laboratory investigations on the role of gamma/delta T cells in Lyme synovitis and a curriculum in immunology, autoimmunity, and the conduct of responsible, clinically relevant research. The candidate will train at the University of Vermont College of Medicine and is a Board-eligible internist with a Ph.D in pharmacology who will be an independent investigator focusing the majority of his efforts on basic research in autoimmunity upon completion of the program. The laboratory project will investigate chronic Lyme arthritis, which presents a model human T lymphocyte infiltrative disease resembling rheumatoid arthritis clinicopathologically, but providing the advantage that the inciting agent, Borrelia burgdorferi, is known. The T lymphocyte infiltrates in Lyme synovitis and rheumatoid arthritis include a striking abundance of gamma/delta T lymphocytes, but the role of this subset in the synovial inflammation remains unclear. Previous work from our laboratory suggests that Lyme synovial gamma/delta T cells proliferate in response to Borrelia burgdorferi and manifest cytolytic activity toward CD4+ T lymphocytes in a Fas-dependent manner. The hypothesis of the research proposal is that Lyme synovial y& cells react to components of B. burgdorferi and modulate the inflammatory response by expression of high and sustained levels of Fas ligand (FasL). This results in cytolytic activity towards activated Fas/high lymphocytes in the inflamed synovium, influencing the in situ immune response.
The specific aims of the research portion of this project are to: 1) define the antigen presenting cells and molecules for borrelia-reactive gamma/delta T cell clones derived from Lyme synovial fluid, and identify the component(s) of B. burgdorferi recognized by these clones, 2) characterize the cytokine phenotype of borrelia-reactive gamma/delta T cell clones. and 3) further characterize the effector function of these clones by measuring the kinetics and stimuli for FasL expression, defining their target cell specificity, and defining any change in the cytokine profile of the synovium that results from differential susceptibility to Fas-mediated cytolysis of various T cell subsets.
| Vincent, Michael S; Xiong, Xiaowei; Grant, Ethan P et al. (2005) CD1a-, b-, and c-restricted TCRs recognize both self and foreign antigens. J Immunol 175:6344-51 |
| Vincent, Michael S; Leslie, David S; Gumperz, Jenny E et al. (2002) CD1-dependent dendritic cell instruction. Nat Immunol 3:1163-8 |
| Leslie, David S; Vincent, Michael S; Spada, Franca M et al. (2002) CD1-mediated gamma/delta T cell maturation of dendritic cells. J Exp Med 196:1575-84 |
| Vincent, M S; Roessner, K; Sellati, T et al. (1998) Lyme arthritis synovial gamma delta T cells respond to Borrelia burgdorferi lipoproteins and lipidated hexapeptides. J Immunol 161:5762-71 |
