EXCEED THE SPACE PROVIDED The goal of this study is to gain an improved understanding of T cell recognition in murine experimental autoimmune encephalomyelitis (EAE) CD4+ T cells which recognize the N-terminal epitope of myelin basic protein (MBPI-11, core ofepitope, MBP1-9) associated with the MHC Class II molecule, I-A u, are the focus of our studies Our recent analyses in H-2 u mice indicate that the avidity ofMBP1-9 I-A u specific T cells for cognate ligand correlates with encephalitogenicity We have also carried out a detailed analysis of the properties of two Tcell receptors (TCRs, '1934 4' and '172 10') derived from MBP1-9 I-A u specific T cells for which TCR transgenic (tg) mice are available These studies show a correlation between TCR affinity and conformational flexibility ('plasticity9 They also suggest that TCR affinity/plasticity might correlate with the susceptibility of the corresponding TCR tg mice to spontaneous disease However, other factors may contribute to, or be solely responsible for, differences in spontaneous disease susceptibility and this possibility will be investigated further here Our hypotheses are First, that T cells expressing TCRs with higher affinity for antigen are more readily triggered than ceils bearing lower aff'mity TCRs Second, that autoreactive, pathogenic T cells express TCRs with distinct kinetics and thermodynamics for ligand binding when compared with TCRs bome by T cells of lower pathogenic potential Third, that it may be possible to combine mutagenesis and functional studies to identify regions of particular TCRs that are responsible for high affinity and/or plastic recognition Our specific alms are 1) to analyze the properties of 172 10 and 1934 4 TCR transgenic T cells, 2) to analyze the affinities, plasticities and cross-reactivities of the TCRs expressed by responding T cells in immunized mice and to con'elate these properties with pathogenicity, 3) to characterize in molecular detail the TCR-pMHC interactions for a subset of the TCRs which have different affinities, plasticities and cross-reactivities These studies should lead to an improved understanding of the factors that lead to the activation of autoreactive T cells and have general relevance to T cell recognition PERFORMANCE SITE ========================================Section End===========================================
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