Daniel W. McVicar, Ph.D.
Dr. McVicar’s laboratory studies the regulation of innate immune cell metabolism and function in cancer. As a member of the Cancer and Inflammation Program, Dr. McVicar uses a variety of cellular and molecular techniques to understand the biology and biochemistry of a variety of receptor systems including the triggering receptors expressed on myeloid cells (TREM) that regulate neutrophils, macrophages, monocytes, dendritic cells and platelets, and the killer Ig-like receptors (KIR) that regulate natural killer (NK) cells. Components of signaling cascades identified by the laboratory are interrogated using murine models of infection and/or inflammation-associated cancers including hepatocellular carcinoma and colorectal cancer.
Receptor-Mediated Regulation of the Innate Immune System
Our laboratory studies the molecular regulation and function of multiple receptor systems involved the generation and propagation of the innate immune response with the goal of understanding how the innate immune system can be harnessed for the prevention of and/or treatment of cancer. More specifically, we have been studying the signal transduction of regulatory receptors of innate immune cells including monocytes/macrophages, natural killer (NK) cells, and most recently, platelets. Receptor systems recently or currently under study include the KIR and the TREM and TREM-Like Receptors. Recent findings have driven us to become interested in the regulation of innate cell metabolic pathways by these receptor systems and the pathways with which they interact.
The Triggering Receptors Expressed on Myeloid Cells (TREM) and TREM-Like Receptors. One of the best-characterized myeloid DAP12-coupled receptor systems are the triggering receptors expressed on myeloid cells (TREM) and TREM-Like Receptors (Treml). The TREM were discovered through screens for proteins capable of facilitating the cell surface expression of DAP12. Subsequent work has characterized a diffuse TREM/TREM-like cluster of receptors that occupies approximately 150 Kbp of murine chromosome 17. The cluster contains 8 characterized genes in the mouse (Trem1, 2, 3, pdcTrem and Treml1, 2, 4, and 6), four of which are conserved in humans (TREM1, TREM2, TREML1, TREMLl2, and TREML4). All members of the family are comprised of a single V-set Ig domain and a moderate stalk region. Five of the eight proteins (TREM-1, 2, 3, PDC-TREM, and Treml-4) have a transmembrane domain with a single charged residue that mediates their physical and functional association with DAP12, followed by short cytoplasmic domains. Treml-1 and Treml-6 have more substantial cytoplasmic tails that include canonical immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and have been shown to interact with the SH-2 domain containing protein phosphatase (SHP)-1. The remaining receptor, Treml-2, has no well-defined cytoplasmic signaling domain.
Relatively little work has been done dissecting the function of the Trem-like receptors. We previously defined a role for Treml1 in sepsis and coagulation. Treml2 regulates neutrophil responses and Treml4 is preferentially expressed on CD8+ DC, Ly6Clo/neg monocytes and red pulp macrophages of the spleen, where it participates in cross presentation of antigen. Recently we have characterized TREM-like Transcript-4 (TREML4) in human leukocytes. We find that TREML4 mRNA is most abundant in neutrophils in the blood and that this mRNA encodes a unique protein unlikely to be expressed on the cell surface. Strikingly, elevated TREML4 expression is associated with coronary artery calcification, and we identified eQTLs in neutrophils and monocytes that define three TREML4 haplotypes. The role of Treml4 in atherosclerosis is currently being studied in mice lacking ApoE and Treml4.
In contrast to the Trem-like receptors, a large body of literature shows that TREM-1 is expressed on monocytes and PMN and is a key regulator of the septic response in mice and humans. In contrast to TREM-1, TREM-2 is expressed on bone marrow-derived macrophages (BMMØ), preosteoclasts, microglia, and immature dendritic cells where it appears to mainly play an anti-inflammatory role. TREM-2 suppresses cytokine production by TLR-stimulated BMMØ and both Trem2-/- and Tyrobp-/- DC are hyper-responsive to TLR stimulation in vitro. Consistent with inhibition of inflammation, TREM-2 is associated with so called “M2”, anti-inflammatory and tissue homeostasis responses; it can be induced in resident peritoneal macrophages with IL-4, it facilitates colon repair following punch biopsy, and it is expressed on alveolar macrophages during allergic inflammation. Accordingly, transduction of myeloid precursors with TREM-2 renders them protective in a model of experimental allergic encephalomyelitis (EAE). TREM-2 has recently received a great deal of attention with the demonstration that relatively rare TREM-2 coding variants are strongly associated with loss of cognitive function in the elderly and with the development of late onset Alzheimer’s disease. Our work has defined a key adaptor protein, Linker for Activated B cells (LAB), in TREM2 signaling in macrophages. Moreover, we find that TREM2, generally thought of as an anti-inflammatory receptor, is involved in amplifying the inflammation associated with DSS-induced colitis and promotes colitis-associated cancer, consistent with TREM regulating interactions with the microbiota. Ongoing work is assessing the potential metabolic regulation of innate immune cells by TREM2 and investigating novel components and pathways involved in the metabolic programing of innate immune cells that takes place during inflammatory responses. Multiple unique targets are under scrutiny.
The Killer Ig-Like Receptors (KIR) of NK Cells. A second interest of the lab is centered on unraveling the regulation of NK cell function by the 3-domain Killer Ig-like Receptors (KIR), KIR3DL1, KIR3DS1, and KIR3DL2 and their role in disease. Both KIR3DL1 and KIR3DS1 have been implicated in the control of HIV disease and certain cancers. Although the binding of KIR3DL1 to HLA Bw4 is well documented and readily detectable, compelling interactions of KIR3DS1 with these ligands has been long sought after. Through extensive international collaborations we have taken a structure:function approach to understanding the basis of the interactions of these receptors with HLA Class I proteins. By dissecting the known interactions between KIR3DL1 and Bw4, we aimed to define molecular characteristics that might reveal ligands for KIR3DS1.
Our initial work identified residues within KIR3DS1 present in some rare KIR3DL1 allotypes, which precluded binding of HLA. We then collaborated with experts in structural analysis to further analyze KIR3DL1/HLA-Bw4 interactions. Our mutagenesis and HLA binding studies defined specific residues of KIR and peptide characteristics involved in this interaction. Based on these characteristics, we have, for the first time, now identified peptides permissive for Bw4 interactions with KIR3DS1. Future work will take a similar approach to KIR3DL2, a framework gene in the KIR cluster associated with cutaneous lymphoma, and psoriatic arthritis. Previous reports have suggested that KIR3DL2 may support the development of Th17 cells, a population known to be critical in autoimmunity and tumor progression. Efforts are underway to investigate the role of KIR3DL2 in disease and dissect the ligand binding properties of this receptor.
Selected Recent Publications
- Am J Hum Genet. 95: 66-76, 2014. [ Journal Article ]
Mutational and structural analysis of KIR3DL1 reveals a lineage-defining allotypic dimorphism that impacts both HLA and peptide sensitivity.J Immunol. 192: 2875-84, 2014. [ Journal Article ]
Environmental factors determine DAP12 deficiency to either enhance or suppress immunopathogenic processes.Immunology. 140: 475-82, 2013. [ Journal Article ]
LAB/NTAL facilitates fungal/PAMP-induced IL-12 and IFN-γ production by repressing ß-catenin activation in dendritic cells.PLoS Pathog. 9: e1003357, 2013. [ Journal Article ]
- Hum Immunol. 73: 783-7, 2012. [ Journal Article ]
Dr. McVicar obtained his Ph.D. from the Medical College of Virginia, Virginia Commonwealth University, where he studied adoptive immunotherapy of brain tumors. He joined the NCI in 1990, completed a postdoctoral fellowship, and attained his current position within the Laboratory of Experimental Immunology in 1998.
|Luke Davies Ph.D.||Research Collaborator|
|Marieli Gonzalez-Cotto Ph.D.||Postdoctoral Fellow (CRTA)|
|Geraldine O'Connor Ph.D.||Guest Researcher|
|Erika Palmieri Ph.D.||Postdoctoral Fellow (Visiting)|
|Christopher Rice Ph.D.||Postdoctoral Fellow (Visiting)|
|Jeffrey Subleski||Research Biologist|
|Jessica Walls||Predoctoral Fellow (Visiting)|
|Jonathan M. Weiss, Ph.D.||Staff Scientist|
Jonathan Weiss, Ph.D., Staff Scientist
Jeffrey Subleski, Biologist
Marieli Gonzalez-Cotto, Ph.D., Postdoctoral Fellow (CRTA)
Erika Palmieri, Ph.D. Postdoctoral Fellow (Visiting)
Christopher Rice, Ph.D., Postdoctoral Fellow (Visiting)
Luke Davies, BSc., Research Collaborator