Antigen Processing & Presentation
A major focus of the lab is directed towards investigating the MHC class II antigen presentation pathway, which is required for antigen recognition by CD4+ T lymphocytes. Peptide binding by class II histocompatibility CD4+ proteins is a critical event in shaping the T cell repertoire and the generation of both adaptive immunity and immunological tolerance. The class II peptide-loading pathway is highly regulated. HLA-DM plays a key role in the MHC class II presentation pathway: catalyzing peptide loading, editing the repertoire of peptides displayed to CD4+ T cells, and acting as a chaperone for empty class II molecules. However, the biochemical mechanisms underlying these functions are poorly understood. Experiments are being done to further investigate the structural basis for DM function and to test the hypothesis that DM is subject to allosteric regulation.
HLA-DO is a highly conserved negative regulator of DM function, buts its biological role remains quite mysterious. Biochemistry and mouse models are being used to investigate the function of HLA-DO. Our working hypothesis is that the primary function of HLA-DO is to broaden the array of self-peptides presented by tolerogenic APC, through attenuation of DM-mediated peptide editing. Additional work is being done to identify other co-factors involved in antigen processing and presentation and factors that regulate subcellular localization and interaction of components of this pathway.
³Non-Classical² Class I MHC (Class Ib) Molecules
This lab is also studying the function of so-called ³non-classical² class I MHC (class Ib) molecules in the immune system. A major focus in this area is on the structure and function of murine Qa-1 and its human counterpart, HLA-E. These molecules can present antigen to a subset of unconventional CD8+ T cells that may have specialized regulatory function. A T cell receptor (TCR) transgenic mouse model was developed to investigate thymic selection and the in vivo function of T cells with this specificity.
Qa-1 and HLA-E have nearly identical peptide binding specificity and they prefer to bind a group of closely related peptides derived from the leader peptides of classical class I molecules. These molecules regulate innate and adaptive immune response by interacting with CD94/NKG2 receptors on NK cells, NK-T, and CD8+ T cells, as well as through antigen presentation to CD8+ T cells. Site-specific mutagenesis and other approaches are underway to investigate the structural basis of the function of Qa-1 and HLA-E. In addition, we have obtained evidence that class Ib-restricted CD8+ T cells can protective immunity in viral infection. Experiments are being done making use of mice that lack all classical MHC molecules to study the magnitude, phenotype, TCR repertoire, and function of polyclonal T cells specific for nonclassical class I molecules.