How TCRs bind MHCs, peptides, and coreceptors

Since the first crystal structure deteminations of alpha beta T cell receptors (TCRs) bound to class I MHC-peptide (pMHC) antigens in 1996, a sizable database of 24 class I and class II TCR/pMHC complexes has been accumulated that now defines a substantial degree of structural variability in TCR/pMHC recognition. Recent determination of free and bound gamma delta TCR structures has enabled comparisons of the modes of antigen recognition by alpha beta and gamma delta T cells and antibodies. Crystal structures of TCR accessory (CD4, CD8) and coreceptor molecules (CD3 epsilon delta, CD3 epsilon gamma) have further advanced our structural understanding of most of the components that constitute the TCR signaling complex. Despite all these efforts, the structural basis for MHC restriction and signaling remains elusive as no structural features that define a common binding mode or signaling mechanism have yet been gleaned from the current set of TCR/pMHC complexes. Notwithstanding, the impressive array of self, foreign (microbial), and autoimmune TCR complexes have uncovered the diverse ways in which antigens can be specifically recognized by TCRs.