Generalists and specialists: a new view of how class I molecules fight disease

J. Kaufman Department of Pathology, University of Cambridge

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©Imperial College London

Classical class I molecules of the major histocompatibility complex (MHC) play crucial roles in defence against viruses.

The class I molecules bind pieces of protein (peptides) from the cytoplasm and nucleus of cells (where viruses replicate) and then move to the cell surface. If class I molecules bearing peptides derived from viruses are recognised by cytotoxic T lymphocytes (CTLs), then the virally-infected cell can be killed by the CTLs.

Viruses are strongly selected to evade the CTLs, for instance by changing the amino acid sequence of the peptides bound to class I molecules, which in turn selects for class I molecules that bind different peptides. This molecular arms race drives MHC molecules to be the most polymorphic genetic loci known.

The genetic associations of the MHC with resistance and susceptibility to infectious pathogens are relatively weak for humans and other mammals, (at least in part) because each MHC haplotype has a multi gene family of class I molecules, all of which together provide more-or-less protection to most pathogens. In contrast, the chicken MHC (that is, the BF-BL region of the B locus) is associated with decisive resistance and susceptibility to economically important infectious diseases, (at least in part) because each MHC haplotype expresses only a single class I molecule, whose properties determine the immune response.

The basis for the difference in the number of class I molecules expressed appears to be the organisation of the MHC, which underwent a genetic inversion in the lineage to placental mammals, breaking co-evolutionary relationships between the class I gene and the genes encoding the antigen processing and peptide loading molecules.

Some MHC haplotypes have a dominantly expressed class I molecule with a fastidious peptide-binding specificity, requiring particular amino acids as anchor residues in at least three positions. However, other haplotypes express a molecule with that binds an astonishing variety of peptides.

The structures of these promiscuous class I molecules explain the breadth of peptide binding. The two kinds of haplotypes differ in a suite of properties, including cell surface expression level, peptide-transporter (TAP) specificity and resistance to the oncogenic herpes virus that causes Marek’s disease.

Looking through the scientific literature, MHC haplotypes with promiscuous class I molecules confer resistance to several different pathogens. Such promiscuous class I molecules might be considered as “generalists” that confer resistance to most pathogens, with particular fastidious “specialists” being selected by new or particularly deadly pathogens.

We examined some human HLA-B molecules and found that they also differ in this suite of properties. Moreover, the highly expressed and fastidious alleles, acting as “specialists”, confer slower progression to acquired immunodeficiency disease syndrome (AIDS) after infection by human immunodeficiency virus (HIV), a relatively new and deadly pathogen. Thus, the concept of “generalists” and “specialists” may be a fundamental property of MHC class I molecules, which is forcing us to re-evaluate decades of immunological research.

From the International Symposium on Avian Corona and Pneumoviruses