Alterations in TCR-MHC contacts subsequent to cross-recognition of class I MHC and singly substituted peptide variants.

Abstract

Vesicular stomatitis virus (VSV) elicits H-2Kb-restricted CTLs specific for the immunodominant VSV octapeptide RGYVYQGL. To study the structural features important for interaction between the TCR beta-chain and the peptide/MHC complex, we immunized TCR alpha-chain transgenic mice with the VSV peptide and raised a panel of anti-VSV CTL clones with identical TCR alpha-chains. Consistent with our previous analysis of uncloned populations of primary CTLs, the anti-VSV CTL clones were all Vbeta13+ and expressed TCR beta-chains with highly homologous complementarity-determining region 3 (CDR3) loops. Although the clones expressed similar TCRs, they differed in their ability to cross-react with VSV peptide variants singly substituted at TCR contact positions 4 and 6. These findings allowed us to identify short stretches of amino acids in the C-terminal region of the CDR3beta loop that, when altered, modify the cross-reaction capability of the TCR to position 4 and position 6 variant peptides. To further probe the structural correlates of biologic cross-reactivity, we used cross-reactive CTL clones and cell lines expressing point mutations in H-2Kb to investigate the effect of single amino acid changes in the peptide on the pattern of recognition of the TCR for the peptide/MHC complex. Single conservative substitutions in the peptide were sufficient to alter the recognition contacts between a cross-reactive TCR and the MHC molecule, supporting the idea that the TCR can make overall structural adjustments in MHC contacts to accommodate single amino acid changes in the peptide.

• Authors: T Ono, T P DiLorenzo, F Wang, A M Kalergis, S G Nathenson
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 161 Issue 10 Pg. 5454-63 (Nov 15 1998) ISSN: 0022-1767 [Print] United States
• PMID: 9820521 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• H-2 Antigens
• Ligands
• Peptide Fragments
• Receptors, Antigen, T-Cell, alpha-beta
• Viral Proteins

Topics

• Amino Acid Substitution (genetics, immunology)
• Animals
• Cell Line
• Clone Cells
• Cytotoxicity, Immunologic (genetics)
• H-2 Antigens (genetics, metabolism)
• Ligands
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Models, Molecular
• Peptide Fragments (genetics, immunology, metabolism)
• Receptors, Antigen, T-Cell, alpha-beta (biosynthesis, genetics, metabolism)
• Sequence Homology, Amino Acid
• T-Lymphocytes, Cytotoxic (immunology, metabolism)
• Vesicular stomatitis Indiana virus (immunology)
• Viral Proteins (genetics, immunology, metabolism)