Molecular basis for recognition of an arthritic peptide and a foreign epitope on distinct MHC molecules by a single TCR.
KRN TCR transgenic T cells recognize two self-MHC molecules: a foreign peptide, bovine RNase 42-56, on I-Ak and an autoantigen, glucose-6-phosphate isomerase 282-294, on I-Ag7. Because the latter recognition event initiates a disease closely resembling human rheumatoid arthritis, we investigated the structural basis of this pathogenic TCR's dual specificity. While peptide recognition is altered to a minor degree between the MHC molecules, we show that the receptor's cross-reactivity critically depends upon a TCR contact residue completely conserved in the foreign and self peptides. Further, the altered recognition of peptide derives from discrete differences on the MHC recognition surfaces and not the disparate binding grooves. This work provides a detailed structural comparison of an autoreactive TCR's interactions with naturally occurring peptides on distinct MHC molecules. The capacity to interact with multiple self-MHCs in this manner increases the number of potentially pathogenic self-interactions available to a T cell.
Basu
D
D
Department of Pathology and Center for Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Horvath
S
S
Matsumoto
I
I
Fremont
D H
DH
Allen
P M
PM
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000276:immunology; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D002417:Cattle; D017124:Conserved Sequence / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism*; D005956:Glucose-6-Phosphate Isomerase / Q000276:immunology / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D008806:Mice, Inbred AKR; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology* / Q000378:metabolism*; D019151:Peptide Library; D011485:Protein Binding / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D012259:Ribonuclease, Pancreatic / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism
D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; C111388:I-Ak antigen; D010446:Peptide Fragments; D019151:Peptide Library; D011948:Receptors, Antigen, T-Cell; D012259:Ribonuclease, Pancreatic; D005956:Glucose-6-Phosphate Isomerase