University of Washington, B.S. Mathematics 1979
University of Minnesota, Ph.D. Genetics 1985
Our laboratory is interested in the genetics of the immune response and the consequential functions of key components. We are examining the essential detail of the genetics and genomics of the immune response in humans and nonhuman primates, detail that differs among individuals and directly affects a plethora of immune interactions and derivative clinical outcomes. In order to identify and understand this detail we are developing novel laboratory approaches combined with essential software to increase both the breadth and depth of information that can be acquired. These tools are being used to identify the causative genetic components underlying common diseases. In functional analysis, we have studied the roles of the nonclassical MHC class I genes HLA-E, F, and G in immunity. A major recent focus has been on understanding HLA-F function, revealing new insights into the role of HLA-F – expressed as an open conformer without peptide or β2-microglobulin – in the regulation of immune system functions and immune defense. This work has extended to a new paradigm for MHC class I open conformer function, including the classical HLA-A, B, and C antigens, intersecting the innate and adaptive immune responses.
Genetic studies of common disease.
The genetics and genomics of the immune response –
A long-term goal of the laboratory has been to facilitate high-throughput, cost effective acquisition of genetic data from immune related genes and genomic regions. Our rationale was based on the belief that in the search for causative genetic factors that underlie common diseases, it is essential to query a broadly inclusive collection of relevant immune response genes at sufficient depth of information to reveal common and rare variation. This is a unique challenge when obtaining genetic data from highly polymorphic loci, a characteristic typical of many genes central to the immune response. For genetic analysis, we developed strategies that significantly improve genotyping for HLA class I and II and Killer Ig-like receptor (KIR) loci, two of the most polymorphic gene families in the human genome. Our workflow includes novel protocols, reagents, and software that extend readily to genotyping at other loci as well. In application, we are currently supporting the FHCRC transplant program and vaccine trials network in association studies of relevant clinical outcomes. For genomic analysis, we are improving methods for complete, haplotype-resolved resequencing across extended genomic subregions, an evident need of genome-wide approaches for identifying causative genetic variation. These methods are currently being used to define the details of multiple MHC and KIR haplotypes from human and nonhuman primate genomes. Both the genetic and genomic approaches are now being applied in the commercial sector through Scisco Genetics Inc.
MHC-I open conformer function in antigen presentation –
HLA-F is expressed as a protein independent of bound peptide or β2-microglobulin and surface expression is upregulated in monocytes and most lymphocyte subsets upon activation. Classical MHC class I (MHC-I) is also expressed on proliferating lymphoid cells as so-called ‘open conformers (OCs)’, in addition to the ubiquitously expressed form complexed with peptide and β2-microglobulin. Our studies showed that HLA-F binds most MHC-I proteins as open conformers without peptide but not as peptide bound complex. This interaction was implicated in the function of HLA-F and MHC-I open conformers in a general mode of exogenous MHC-I antigen uptake and presentation by activated immune cells that differs in significant detail from endogenous antigen presentation. These studies were further extended to show that both HLA-F and MHC-I OC are ligands for a specific subset of killer Ig-like receptors (KIRs), defining a new paradigm for MHC-I function and communication between the innate and acquired immune responses. A long-term extension of our work is to dissect the HLA-F/MHC-I OC pathway to uncover the requirements for antigens to access the pathway. We are currently testing the hypothesis that antigen entry is governed by a synergy between specific structural characteristics of the exogenous antigen and the MHC-I allele types of the target cells. A goal is to manipulate these features to optimize antigen uptake and presentation in designing effective immunogens for directed stimulation of antigen-specific host responses.
The immunology of pregnancy –
During pregnancy, direct contact between the maternal immune system and the placental allograft and accompanying tolerance to paternally derived antigens contributes a unique immune compartment. Understanding the mechanisms in play in this ‘alternate’ immune response will provide new avenues towards enabling the health of the mother and child. Moreover, such knowledge will have application in a number of other clinical arenas including transplantation, autoimmunity, and tumor immunology. The overall goal of our research in the immunology of pregnancy is to understand the function of HLA-F in the context of MHC-I as expressed in the pregnant environment. Our central hypothesis is that HLA-F plays a key role in receptor-ligand interactions between trophoblasts and decidual NK (dNK) cells. As a corollary, we postulate that HLA-F acts cooperatively with other MHC-I expressed in extravillous trophoblasts to modulate their interactions with receptors on dNK, and that these interactions contribute to the immunoregulatory and growth regulatory functions of those cells. These modulations are likely specific to the placental environment – where HLA-E, F, G and C are co-expressed – conceptually similar to the enhanced specificity of HLA-E for activating CD94/NKG2 receptors conferred by the HLA-G derived nonamer peptide. We are currently testing our hypotheses at several levels by directly examining genetic interactions with pregnancy-related disease, defining biochemical interactions of MHC-I and NK receptors, and relating those data to functional interactions between trophoblasts and dNK cells.