Our Science – McVicar Website
Daniel W. McVicar, Ph.D.
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 cells, and most recently, Platelets. Receptor systems recently or currently under study include the Ly49s, KIR, Siglecs, PIR, and TREM.
DAP12 as a central figure in Paired Immune Receptor Systems
DAP12 is Immunoreceptor Tyrosine Based Activation Motif (ITAM)-containing signal transduction chain first described in association with members of the Ly49 receptor family in murine NK cells, and the Killer Immunoglobulin-like Receptors (KIR) of human NK cells. Association of DAP12 delineates the activating receptors of these families from their more widely appreciated inhibitory counterparts. It has now been shown that DAP12 mediates the signaling of a variety of receptors other than the KIR and Ly49s suggesting that the chain may play a central role in innate immunity. Our laboratory has, therefore, been investigating the signal transduction of DAP12-coupled receptors. Our studies have shown a curious lack of DAP12 reactivity in the NK cells of 129/sv mice that may explain some of the unique immunobiology of this strain. In addition, we have been dissecting the proximal signaling events associated with DAP12 ligation and found that Fyn plays an important role downstream of CD45 and upstream of Syk. Interestingly, many of these non-NK cell DAP12-coupled receptors are found within the myeloid lineage suggesting an important role for the signaling chain within this compartment. Our ongoing studies of DAP12 signaling in monocytes/macrophages should help to understand the role these receptors play in myeloid biology.
The Triggering Receptors Expressed on Myeloid Cells (TREM)and TREM-like Transcripts
One of the best-characterized myeloid DAP12-coupled receptor systems are the Triggering Receptor Expressed on Myeloid Cells (TREM). To date, three activating TREMs have been described forming a loose cluster occupying a 150kb region of human chromosome 6 and murine chromosome 17. TREM-1 is broadly expressed on neutrophils and monocytes and is involved in the response to LPS. TREM-2 is expressed on monocytes, macrophages, osteoclasts, and dendritic cells and is the gene mutated in polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL, a.k.a. Nasu-Hakola Disease), a rare inherited disorder associated with systemic bone cysts and psychotic symptoms that rapidly progress to presenile dementia and death. TREM-3 also associates with DAP12 and activates murine macrophages when ligated. We closely examined the TREM locus in an effort to uncover an inhibitory receptor that might serve to balance the activators within the cluster and identified a gene we have named TREM-like transcript (TLT)-1. We have found that TLT-1 does not couple to DAP12, instead, its longer cytoplasmic tail carries a canonical immunoreceptor tyrosine-based inhibitory motif (ITIM) capable of becoming phosphorylated and binding Src Homology containing protein tyrosine phosphatase (SHP)-1. These data make TLT-1 as the only putative inhibitory member of the TREM cluster. Interestingly, although initial analysis of TLT-1 expression suggested it would act as a TREM regulator, our most recent detailed analysis found TLT-1 to be expressed exclusively in megakaryocytes and platelets. Further we found that within platelets TLT-1 is sequestered within the alpha granules. These granules rapidly release their contents upon platelet activation. The result is a 5-10 fold up-regulation of surface TLT-1. These data demonstrate that TLT-1 likely plays an important role thrombosis and/or vascular homeostasis. Ongoing studies include the characterization of TLT-1-/- mice and identification of the TLT-1 ligand. In addition, we are harnessing the secretory and storage capacity of megakaryocytes and platelets for targeted delivery of biotherapeutics to tumors and/or tumor vasculature.
This page was last updated on 6/7/2013.