Abstract

Highly polymorphic major histocompatibility complex (MHC) molecules are at the heart
of adaptive immune responses, playing crucial roles in many kinds of disease and in vaccination. We
report that breadth of peptide presentation and level of cell surface expression of class I molecules
are inversely correlated in both chickens and humans. This relationship correlates with protective
responses against infectious pathogens including Marek’s disease virus leading to lethal tumours in
chickens and human immunodeficiency virus infection progressing to AIDS in humans. We propose
that differences in peptide binding repertoire define two groups of MHC class I molecules
strategically evolved as generalists and specialists for different modes of pathogen resistance. We
suggest that differences in cell surface expression level ensure the development of optimal
peripheral T cell responses. The inverse relationship of peptide repertoire and expression is evidently
a fundamental property of MHC molecules, with ramifications extending beyond immunology and
medicine to evolutionary biology and conservation.