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Chain on Major Histocompatibility Complex
(MHC) Class II + Peptide Recognition
By
§§
¶¶
From the * Howard Hughes Medical Institute, The Department of Medicine, National Jewish Medical and
Research Center, and § Department of Immunology, Department of Biochemistry, Biophysics and
Genetics, and ¶ Department of Medicine, University of Colorado Health Sciences Center, Denver,
Colorado 80206
/
T cell receptor (TCR) recognizes peptide fragments bound in the groove of major
histocompatibility complex (MHC) molecules. We modified the TCR chain from a mouse
T cell hybridoma and tested its ability to reconstitute TCR expression and function in an chain-deficient variant of the hybridoma. The modified chain differed from wild type only
in its leader peptide and mature NH2-terminal amino acid. Reconstituted cell surface TCR complexes reacted normally with anti-TCR and anti-CD3 antibodies. Although cross-linking
of this TCR with an antibody to the TCR idiotype elicited vigorous T cell hybridoma activation, stimulation with its natural MHC + peptide ligand did not. We demonstrated that this
phenotype could be reproduced simply by substituting the glutamic acid (E) at the mature NH2
terminus of the wild type TCR chain with aspartic acid (D). The substitution also dramatically reduced the affinity of soluble /-TCR heterodimers for soluble MHC + peptide molecules in a cell-free system, suggesting that it did not exert its effect simply by disrupting TCR
interactions with accessory molecules on the hybridoma. These results demonstrate for the first
time that amino acids which are not in the canonical TCR complementarity determining regions can be critical in determining how the TCR engages MHC + peptide.
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