MHC Interaction

Abstract: Studies of TCR expression in antigen-specific immune responses have provided a large body of information correlating the primary structure of the TCR with specificity. Much has been learned regarding the mechanisms for the generation of TCR diversity and the selection of TCR V elements in immune responses. However, the exact nature of the trimolecular complex found during the TCR/antigen/MHC interaction awaits the structural characterization of the TCR by crystallography. Just as describing the three-dimensional structure of MHC molecules and defining their putative antigen-binding site have made it possible to interpret with fresh insight the wealth of functional data regarding antigen/MHC binding and alloreactivity, similar characterization of the TCR structure will allow more definitive interpretation of all the current data with respect to TCR usage in antigen-specific immune responses. It should also facilitate the study of the molecular basis of positive and negative TCR selection during thymic ontogeny. Finally, the identification of T-cell superantigens and their ability to stimulate T cells on the basis of TCR V beta expression alone has defined a new and distinct type of TCR/ligand interaction. The fact that bacterial products such as staphylococcal and streptococcal toxins as well as the mitogenic moiety produced by some mycoplasma are included within this class of antigens suggests that TCR recognition of superantigens may have major clinical significance. It is important to determine the structural basis of T-cell activation by these antigens.

Abstract: While recent evidence strongly suggests that the third complementarity determining regions (CDR3s) of T cell receptors (TCRs) directly contact antigenic peptides bound to major histocompatibility complex (MHC) molecules, the nature of other TCR contact(s) is less clear. Here we probe the extent to which different antigens can affect this interaction by comparing the responses of T cells bearing structurally related TCRs to cytochrome c peptides and staphylococcal enterotoxin A (SEA) presented by 13 mutant antigen-presenting cell (APC) lines. Each APC expresses a class II MHC molecule (I-Ek) with a single substitution of an amino acid residue predicted to be located on the MHC alpha helices and to point "up" towards the TCR. We find that very limited changes (even a single amino acid) in either a CDR3 loop of the TCR or in a contact residue of the antigenic peptide can have a profound effect on relatively distant TCR/MHC interactions. The extent of these effects can be as great as that observed between T cells bearing entirely different TCRs and recognizing different peptides. We also find that superantigen presentation entails a distinct mode of TCR/MHC interaction compared with peptide presentation. These data suggest that TCR/MHC contacts can be made in a variety of ways between the same TCR and MHC, with the final configuration apparently dominated by the antigen. These observations suggest a molecular basis for recent reports in which either peptide analogues or superantigens trigger distinct pathways of T cell activation.