I-Aα polymorphic residues that determine alloreactive T cell recognition

Abstract

An individual's T lymphocytes are highly reactive to allogenic MHC molecules. As a step in deciphering the mechanism of allorecognition by T lymphocytes, we have attempted to identify the TCR's target on MHC class II molecules, in particular the polymorphic residues that determine the specificity of recognition. We have generated a panel of A(k)-reactive, Ab-nonreactive T cell hybridomas, and sets of L cell transfectants displaying AαAβ molecules with wild-type, chimeric or single site-mutated Aα chains, with reciprocal interchanges between A(k) and Ab. We then measured the stimulation of the T hybridomas in response to the transfectants. The results indicate that the hybridomas recognize diverse and complex determinants, with contributions from both Aα and Aβ chains, and from several regions or amino acids of the Aα chain. The data are most consistent with a model in which alloreactivity results from the presentation of peptides to the T cell by an allogenic MHC molecule, peptides that cannot be presented by the responder's own MHC complexes. The specificity of allorecognition seems to be imparted mainly by peptide/MHC molecule rather than TCR/MHC molecule contacts.