Coevolution of TCR-MHC interactions: conserved MHC tertiary structure is not sufficient for interactions with the TCR.
The specificity for self-MHC that is necessary for T cell function is a consequence of intrathymic selection during which T cell antigen receptors (TCRs) expressed by immature thymocytes are tested for their affinity for self-peptide:self-MHC. The germ-line-encoded segments of the TCR, however, are believed to have an innate specificity for structural features of MHC molecules. We directly tested this hypothesis by generating a transgenic mouse system in which the protein HLA-DM is expressed at the surface of thymic cortical epithelial cells in the absence of classical MHC molecules. The specialized intracellular function of HLA-DM has removed this MHC class II-like protein from the evolutionary forces that have been hypothesized to shape TCR-MHC interactions. Our study shows that a structural mimic of MHC class II is not sufficient to appropriately interact with the TCRs expressed by developing thymocytes. This result emphasizes the unique complementarity of TCR-MHC interactions that are maintained by the evolutionary pressures dictated by positive selection.
Kim
Hye-Jung
HJ
Laboratory of T Cell Immunobiology, Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Guo
Donglin
D
Sant'Angelo
Derek B
DB
D000818:Animals; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000235:genetics; D019143:Evolution, Molecular; D005434:Flow Cytometry; D006681:HLA-D Antigens / Q000235:genetics / Q000276:immunology*; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism*; D014162:Transfection
D018076:DNA, Complementary; D006681:HLA-D Antigens; C084245:HLA-DM antigens; D011948:Receptors, Antigen, T-Cell