HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Brawley, J. V. Articles by Concannon, P. Search for Related Content PubMed PubMed Citation Articles by Brawley, J. V. Articles by Concannon, P.

Systematic Mutagenesis of TCR Complementarity-Determining Region 3 Residues: A Single Conservative Substitution Dramatically Improves Response to Both Multiple HLA-DR Alleles and Peptide Variants¹

Molecular Genetics Program, Virginia Mason Research Center, Seattle, WA 98101; and Department of Immunology, University of Washington, Seattle, WA 98195

To define the relative contributions of HLA and peptide contacts with TCR complementarity-determining region (CDR) 3 residues in T cell recognition, systematic mutagenesis and domain swapping was conducted on two highly similar TCRs that both respond to the influenza hemagglutinin (HA) peptide, HA_307–319, but with different HLA restrictions. Despite the primary sequence similarity of these TCRs, exchange of as little as two CDR3 residues between them completely abrogated responsiveness. At position 95 within CDR3, various substitutions still allowed for some degree of recognition. One modest substitution, alanine for glycine (essentially the addition of a methyl group), significantly broadened the specificity of the TCR. Transfectants expressing this mutant TCR responded strongly in the context of multiple HLA-DR alleles and to HA peptide variants with substitutions at each TCR contact residue. These results suggest that the conformations of CDR3 loops are crucial to TCR specificity and that it may not be reliable to extrapolate from primary sequence similarities in TCRs to similarities in specificity. The ease with which a broad specificity is induced in this mutant TCR has implications for the mechanisms and frequency of alloreactivity and promiscuity in T cell responses.

This article has been cited by other articles:

				X. Xi, Y. Guo, H. Chen, C. Xu, H. Zhang, H. Hu, L. Cui, D. Ba, and W. He Antigen Specificity of {gamma}{delta} T Cells Depends Primarily on the Flanking Sequences of CDR3{delta} J. Biol. Chem., October 2, 2009; 284(40): 27449 - 27455. [Abstract] [Full Text] [PDF]

				J. V. Brawley and P. Concannon Complementarity-Determining Region 1 Sequence Requirements Drive Limited V{alpha} Usage in Response to Influenza Hemagglutinin 307-319 Peptide J. Immunol., April 15, 2002; 168(8): 3894 - 3901. [Abstract] [Full Text] [PDF]

				K. D. Bourcier, D.-G. Lim, Y.-H. Ding, K. J. Smith, K. Wucherpfennig, and D. A. Hafler Conserved CDR3 Regions in T-Cell Receptor (TCR) CD8+ T Cells That Recognize the Tax11-19/HLA-A*0201 Complex in a Subject Infected with Human T-Cell Leukemia Virus Type 1: Relationship of T-Cell Fine Specificity and Major Histocompatibility Complex/Peptide/TCR Crystal Structure J. Virol., October 15, 2001; 75(20): 9836 - 9843. [Abstract] [Full Text] [PDF]

				J. Vollmer, H. U. Weltzien, K. Gamerdinger, S. Lang, Y. Choleva, and C. Moulon Antigen contacts by Ni-reactive TCR: typical {alpha}{beta} chain cooperation versus {alpha} chain-dominated specificity Int. Immunol., December 1, 2000; 12(12): 1723 - 1731. [Abstract] [Full Text] [PDF]