T cells that express the gamma delta T cell receptor (TCR) form a distinct population of lymphocytes whose exact role remains unclear. Phenotypic and functional studies suggest that although these cells share many features in common with T cells, they also share properties with natural killer (NK) cells, and even B cells. These observations have led to the suggestion that gamma delta cells serve a unique role within the immune response that perhaps reflects their ability to recognize and respond to a particular set of ligands. Interestingly, however, little is known with certainty about the nature of the ligands involved in this response, or the extent to which these cells form an essential part of the immunological network. The investigator's studies have focused on the contribution of these cells to inflammatory demyelinating diseases of the nervous system, such as multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Their data have led them to generate the hypothesis that certain populations of gamma delta T cells function to accelerate the inflammatory process by either serving as a source of proinflammatory cytokines and chemokines or inducing them at sites of inflammation. They further propose that this population of gamma delta T cells is activated by ligands found on a number of common pathogens and/or are expressed by stressed host cells. As such they propose that they represent a subpopulation of """"""""natural T cells"""""""" that form a bridge between the innate and acquired immune response. To test this hypothesis three aims are proposed. In the first they will investigate the contributions of gamma delta T cells to the development of EAE in TCRdelta-/- mice. In preliminary studies they have found that MOG-induced EAE in TCRdelta-/- mice shows a significant and highly reproducible delay in disease onset. In this aim they propose to determine in what way gamma delta T cells contribute to the inflammatory process. In the second aim, they will explore the signals that lead to the activation and recruitment of these cells to the CNS compartment. They will test the hypothesis that gamma delta T cells in EAE are activated and recruited by antigen-specific alpha beta T cells, or by changes mediated by these cells, at sites of antigen recognition in the CNS. In the third specific aim they plan to continue their studies on the properties of gamma delta T cells in the marmoset model of EAE. The overall goal of these studies is to investigate the functional properties of gamma delta T cells in autoimmune-mediated diseases of the central and peripheral nervous system. Their hope is that the information to be obtained will provide additional insights into the pathogenic mechanisms involved in the initiation of inflammation at these sites that would be of value in designing effective anti-inflammatory therapies.
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