MHC Evolution and Development of a Recognition System

The unrestricted viability of allophenic mice shows that MHC-different cell lines have no problem engaging in organogenesis together. Thus, outside of the immune system, mammals appear to have no self-non-self discrimination mechanism based on polymorphic and ubiquitously expressed class I MHC antigens. Here, it should be pointed out that even within the immune system, certain responses require no self-non-self discrimination, for example, antiphosphocholine response and certain antipolysaccharide responses that exploit differences between bacterial and host sugar transferases. Thus, the self-non-self discrimination via peptide fragments presented by ubiquitously expressed class I MHC antigens can be viewed as the late addition that enabled the adaptive immune system to cope with intracellular parasites that are primarily viruses. The preference for different types of peptide fragments suffices to explain extensive polymorphism as well as multiple gene loci for class I and possibly also class II MHC antigens. Yet, a too specialized class I MHC allele that presents a very unusual peptide fragment is of no use, for such a peptide fragment is not likely to be found among viral proteins. Effective MHC antigens are those that prefer common enough peptide fragments, so that at least one T epitope can be found in one out of every three viral proteins. Yet, such common peptide fragments are also likely to be present among multitudes of intracellular proteins that are the self. The immune system appears to have solved the above dilemma by mounting a vigorous cytotoxic T-cell response only when viruses are actively propagating by synthesizing a few of their own proteins in large amounts, thereby suppressing the host protein synthesis. To attack infected cells in which viruses are in the quiescent state of symbiosis with the host is the ultimate folly.