Molecular Basis of Immunological Tolerance and Non-Response

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Immunological tolerance is established by elimination or inactivation of self-reactive T cells through TCR-MHC-peptide interaction in the thymus or periphery. To better understand the molecular mechanism for immunological tolerance, we focused on the generation of MHC/peptide complex and its recognition by TCRs, and obtained several new findings.We revealed that HLA-DM functions as an editor of MHC class II-binding peptides. This would raise the new possibility that the kinetic stability of MHC class II/peptide complex play a important role in tolerance induction. The development and analysis of transgenic-knockout mouse lines expressing a single MHC class IIIpeptide complex brought several new insights into T cells repertoire selection. In addition, we found that organ-specific autoimmunity spontaneously develops in one of such mouse lines, which would argue against the currently prevailing paradigm for MHC class II association with autoimmune diseases.