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Amino acid substitutions in the first complementarity-determining region of a murine T-cell receptor alpha chain
E A Nalefski1, J G Wong, A Rao
1Division of Tumor Virology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115.
The T-cell antigen receptor mediates recognition of foreign antigens physically associated with major histocompatibility complex (MHC) proteins. The tertiary structure of the T-cell receptor is thought to resemble that of immunoglobulin Fab fragments and to possess corresponding complementarity-determining regions (CDRs) that contact antigen-MHC. To test such a model for the T-cell receptor, we have generated T-cell hybridomas that express a wild-type or mutant form of the T-cell receptor present on the p-azobenzenearsonate-specific T-cell clone D5. Mutation of 2 amino acids (Tyr26 to serine, Gly28 to valine) in the predicted CDR1 of the D5 T-cell receptor alpha chain caused a markedly diminished response to antigen without affecting the response to anti-CD3 and anti-T-cell receptor antibodies. These results constitute the first test of the prediction that CDR1 in the T-cell receptor alpha chain is important for antigen-MHC recognition, thus providing strong evidence for the structural model of the T-cell antigen receptor based upon immunoglobulin.
The T-cell antigen receptor mediates recognition of foreign antigens physically associated with major histocompatibility complex (MHC) proteins. The tertiary structure of the T-cell receptor is thought to resemble that of immunoglobulin Fab fragments and to possess corresponding complementarity-determining regions (CDRs) that contact antigen-MHC. To test such a model for the T-cell receptor, we have generated T-cell hybridomas that express a wild-type or mutant form of the T-cell receptor present on the p-azobenzenearsonate-specific T-cell clone D5. Mutation of 2 amino acids (Tyr26 to serine, Gly28 to valine) in the predicted CDR1 of the D5 T-cell receptor alpha chain caused a markedly diminished response to antigen without affecting the response to anti-CD3 and anti-T-cell receptor antibodies. These results constitute the first test of the prediction that CDR1 in the T-cell receptor alpha chain is important for antigen-MHC recognition, thus providing strong evidence for the structural model of the T-cell antigen receptor based upon immunoglobulin.