Molecular basis for T cell repertoire selection in the thymus

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T cell repertoire is shaped through the recognition of MHC/self-peptide complex by TCRs in the thymus. However, diversity of self-peptide precluded analyzing this interaction at a molecular level. To overcome this problem, we have developed transgenic-knockout mice where MHC molecules are occupied with a single defined peptide. By analyzing these mice, we found that 1) the same MHC/peptide complex, being affected by its expression level in the thymus, can serve as a ligand for both positive and negative selection and 2) while specific TCR-peptide interaction is involved even in positive selection, the amino acid residue of the peptides at TCR-contact remarkably affects the diversity of the selected T cell repertoire. On the other hand, it is well known that particular MHC alleles are associated with the susceptibility to organ-specific autoimmune diseases. We found that a line of transgenic-knockout mice expressing a single MHC/peptide complex at a quite low level in the thymus spontaneously develops peripheral nervous-specific autoimmune diseases. Since MHC molecules are accupied with a single defined peptide in these mice, these results suggest that MHC molecules determine the susceptibility to autoimmune diseases through T cell repertoire selection in the thymus.