The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/6/1919/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 11, June 2, 1997 1919-1927


Articles

Influence of the NH2-terminal Amino Acid of the T Cell Receptor {alpha} Chain on Major Histocompatibility Complex (MHC) Class II + Peptide Recognition

Jeffrey L. Seibel{ddagger},§, Nancy Wilson*,{ddagger}, Haruo Kozono{ddagger}, Philippa Marrack*,{ddagger},§,||, and John W. Kappler*,{ddagger}

From the * Howard Hughes Medical Institute, {ddagger} 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

The {alpha}/β T cell receptor (TCR) recognizes peptide fragments bound in the groove of major histocompatibility complex (MHC) molecules. We modified the TCR {alpha} chain from a mouse T cell hybridoma and tested its ability to reconstitute TCR expression and function in an {alpha} chain–deficient variant of the hybridoma. The modified {alpha} 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 {alpha} chain with aspartic acid (D). The substitution also dramatically reduced the affinity of soluble {alpha}/β-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.


Address correspondence to Dr. Philippa Marrack, National Jewish Center for Immunology and Respiratory Medicine, Goodman Bldg., 5th Floor, 1400 Jackson St., Denver, CO 80206.


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