Current Research and Scholarly Interests
The Parham laboratory investigates the biology, genetics, and evolution of Major Histocompatibility Complex (MHC) class I molecules, natural killer (NK) cell receptors, and other immune system molecules. Classical MHC class I molecules are peptide-binding glycoproteins expressed on the surface of most vertebrate cells where they interact with the receptors of cytolytic CD8+ T lymphocytes and NK cells of the immune system. Both these types of killer lymphocytes are important for defence against viruses - generalised NK cell response at the beginning of infection, and specific T cell response further on if the pathogen is not eliminated by innate immunity. The rapid evolution of viruses selects for diversity of MHC class I molecules within populations of humans and other vertebrates. One consequence of this diversity is that MHC class I difference is a major immunological barrier to tissue transplants between unrelated donors and patients. A second consequence is that MHC class I molecules of different taxonomic species are very different, for example, there is no true orthologue between the classical class I genes of humans and mice. Whereas once considered homogeneous, NK cells are now shown to have both clonal diversity arising from differential expression of NK cell receptors within an individual, and population diversity in haplotype content and gene polymorphism. Clinical consequences analogous to those for MHC class I are expected due to NK cell receptor diversity. In humans, NK cell receptors consist of both immunoglobulin-like molecules and lectin-like molecules, however, only the lectin-like receptors are functional homologues in mice. As with their MHC class I ligands, NK cell receptors have also undergone rapid evolution.
One goal of our research is to understand how the continual battle between vertebrates and viruses has driven the diversification and divergence of MHC class I molecules and NK cell receptors. In human, we examine the polymorphism of NK receptor genes in different populations which are shaped by different histories of pathogen encounters. We also examine the coevolution of MHC class I and NK receptor genes in two close cousins of human, the chimpanzee and the orangutan.
A second goal is to understand the molecular and biochemical interactions between NK cell receptors and their MHC class I ligands. We perform mutagenesis studies to fine map interactions between NK cell receptors and MHC class I molecules. We also examine essential residues that determine the expression or retention of NK cell receptor alleles.
A third goal is to understand how MHC class I and NK cell receptor differences influence the outcomes of clinical transplantation. We follow the recovery of NK cell populations in leukemia and lymphoma patients after bone-marrow transplants and correlate the reconstitution of NK cell with the donor's and patient's genotypes, therapies and clinical consequences.