Why peptides? Their possible r01e in the evolution of MiIGrestrid T-cell recognition

The peptide-presenting function of major histocompatibility complex (MHQ molecules permits pathogenic microorganisms to evade the host's immune system in two different ways: first, by escape of pathogen-derived antigenic peptides from presen- tation, and second, by molecular mimicry, that is resemblance between MHC-bound serf and foreign peptides. These two mechanisms could have served as selective pressures in the evolution of the MHC In this article, Zoltan Nagy and col. leagues icmpose that escape from presentation selec~ for one or a few MHC molecules with the capacity to bind a broad range of different peptJdes. In contrast, molecular mimicry is considered to be the driving force for MHC diversification, that is it increases the number (polymotphism) and selectivity of peptide-binding sites. There is now ample evidence to show that T cells recognize foreign antigen in the form of short peptides associated with MHC molecules 1-3. The recently re- ported three-dimensional structure of an MHC class I molecule supports a peptide-binding function for MHC dass I and probably also for MHC c~a~s ii molecules 4-6. Apparently, the first and second domains of the class I molecule (and the amino-terminal domains of the two class II chains) form a binding site capable of accommo- dating peptides. Because most of the amino acid resi- dues that differ among allelic forms of MHC molecules ('polymorphic residues') are found in and around this binding site, allele-dependent differences are expected in been shown to be the case ~.2.7,8. However, the binding size should not exhibit a high degree of specificity (like antibodies, for example), because each individual has only a small set of different MHC molecules functioning in peptide presentation (for example three class I, and one or two class II molecules per haplotype in the mouse), and this set must interact with a very large number of antigenic peptides. Thus, each MHC molecule should bind a whole array of different peptides, and this has been shown to be the case 7,8. Undoubtedly, the physico-chemical basis for peptide-MHC interaction will also be clarified soon 9.~0. However, despite overwhelm- ing experimental evidence in its support, the notion of a peptide-centered T-cell system is not easy to rationalize, since no conceptual framework ~ available for under- standing its biological significance and the selective pressures involved in its evolution. In this article, we will try to place the complex phenomena involved in pep- tide-MHC-T-cell interactions into an evolutionary perspective. Pros and cons of peptide presentation and recognition