Journal of Experimental Medicine, Vol 179, 213-219, Copyright © 1994 by Rockefeller University Press

ARTICLES

Conformational differences in major histocompatibility complex-peptide complexes can result in alloreactivity

S Chattopadhyay, M Theobald, J Biggs and LA Sherman
Department of Immunology, Scripps Research Institute, La Jolla, California 92037.

Mutations within the class I major histocompatibility complex (MHC) molecule that affect a peptide binding can result in strong allogeneic responses. It is believed this reflects, in part, binding of a different set of endogenous peptides by each MHC molecule. We have examined the representation of allopeptides recognized by Kb-specific cytotoxic T lymphocytes (CTL) clones among targets that express either the Kb or the Kbm8 mutant. These class I molecules mutationally differ by several residues at the base of the peptide binding groove resulting in lack of recognition of bm8 targets by most Kb-specific CTL, and in strong mutual alloreactivity. Since these differences involve pockets in the base of the peptide binding groove that are presumed to contribute to the affinity of peptide binding, and there is evidence for differences in peptide binding by the mutant and wild type molecule, it was considered most likely that alloreactivity was due to binding of different sets of peptides by each of these molecules. Surprisingly, the allopeptides recognized by Kb-specific clones from a variety of responders, including bm8, are often found associated with both the wild type and mutant class I molecules. Although for some allopeptides the amount of peptide normally found associated with bm8 is less than that associated with Kb, reactivity could not be restored by increasing the amount of the relevant peptide. Thus, the basis for much of the alloreactivity observed in this particular mutant and wild type combination is not the presence or absence of the relevant allopeptide but rather the different conformation adapted by the peptide-MHC complex. These results allow us to conclude that strong alloreactive responses can result from T cell recognition of conformational differences between the stimulation and responder MHC molecules.
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