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 (MBP1-11, core of epitope, MBP1-9) associated with the MHC Class II molecule, I-Au, are the focus of our studies. Our recent analyses in H-2u mice indicate that the avidity ofMBP1-9 I-Au specific T cells for cognate ligand correlates with encephalitogenicity. We have also carried out a detailed analysis of the properties of two T cell receptors (TCRs, '1934 4' and '172.10') derived from MBP1-9 I-Au specific T cells for which TCR transgenic (tg) mice are available These studies show a correlation between TCR affinity and conformational flexibility ('plasticity'). 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 cells bearing lower affinity TCRs. Second, that autoreactive, pathogenic T cells express TCRs with distinct kinetics and thermodynamics for ligand binding when compared with TCRs borne 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 aims 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 correlate 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.
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