The experimentally-induced autoimmune disease, experimental allergic encephalomyelitis (EAE), is the consequence of an inflammatory process initiated by the interaction of neuroantigen-specific T cells with antigenic peptides presented by MHC class II+ antigen presenting cells (APC) in the CNS. The dynamics of the CNS T cell population during acute and relapsing EAE is an important aspect of this disease particularly with respect to the design of immunotherapeutic protocols. An important issue is the mechanism by which the encephalitogenic activity of neuroantigen-specific T cells is regulated in the normal animal as well as during the course of chronic relapsing EAE. We have found that normal regulatory activity is absent in TCR beta-chain knockout (alpha/betaTCR-/-) mice. Preliminary characterization of the regulatory cell population in wild-type mice indicates that the phenotype of the regulatory cell is CD4- CD8-NK1.1+alpha/betaTCR+ or CD4-CD8+NK1.1+alpha/betaTCR+. The hypothesis to be tested is that one or both of these phenotypes is responsible for down-regulation of EAE effector T cells. To test this hypothesis the following Specific Aims are proposed, 1) to assess the role of NK1.1+ alpha/beta+ T cells in recovery from passive EAE using B6 mice with targeted mutations of the immune system, 2) to assess the role of NK1.1+ alpha/beta+ T cells in regulation of self-reactive T cells in the normal individual using B6 mice with targeted mutations of the immune system, 3) to investigate the mechanism of regulation of self-reactive T cells by NK1.1+ alpha/beta+ T cells, 4) to analyze heterogeneity of the a and P-chain CDR3 regions of NK1.1+ alpha/beta+ T cells by spectratypic analysis and nucleotide sequence, and 5) to analyze the interaction of NK1.1+ alpha/beta+ T cells with self-reactive T cells.
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