Molecular basis for recognition of an arthritic peptide and a foreign epitope on distinct MHC molecules by a single TCR

J Immunol. 2000 Jun 1;164(11):5788-96. doi: 10.4049/jimmunol.164.11.5788.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution / immunology
  • Animals
  • Arthritis, Rheumatoid / enzymology
  • Arthritis, Rheumatoid / immunology*
  • Arthritis, Rheumatoid / metabolism*
  • Cattle
  • Conserved Sequence / immunology
  • Epitopes, T-Lymphocyte / immunology
  • Epitopes, T-Lymphocyte / metabolism*
  • Glucose-6-Phosphate Isomerase / immunology
  • Glucose-6-Phosphate Isomerase / metabolism
  • Histocompatibility Antigens Class II / immunology
  • Histocompatibility Antigens Class II / metabolism*
  • Humans
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred AKR
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Transgenic
  • Molecular Sequence Data
  • Peptide Fragments / immunology*
  • Peptide Fragments / metabolism*
  • Peptide Library
  • Protein Binding / immunology
  • Receptors, Antigen, T-Cell / metabolism*
  • Ribonuclease, Pancreatic / immunology
  • Ribonuclease, Pancreatic / metabolism
  • T-Lymphocytes / enzymology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism

Substances

  • Epitopes, T-Lymphocyte
  • Histocompatibility Antigens Class II
  • I-Ak antigen
  • Peptide Fragments
  • Peptide Library
  • Receptors, Antigen, T-Cell
  • Ribonuclease, Pancreatic
  • Glucose-6-Phosphate Isomerase