The Triggering Receptors Expressed on Myeloid Cells (TREM) are expressed on a variety of innate immune cells including monocytes, macrophages, dendritic cells (DC), neutrophils, and osteoclasts. These receptors deliver signals to their host cells via association with the signaling chain, DAP12. DAP12 signaling is dependent on the presence of an immunoreceptor tyrosine-based activation motif (ITAM) within its cytoplasmic tail. Upon stimulation of a DAP12-coupled receptor, DAP12 is phosphorylated and recruits proteins critical to the propagation of downstream signals. Recent work has demonstrated that members of the TREM family, via DAP12, can deliver either activation or inhibitory signals to monocytes and macrophages. However, the biochemical nature of DAP12 signaling within myeloid cells is largely uncharacterized as is the overall immunological role of the TREM gene cluster. Thus, we have taken a bipartite approach to understand the immunobiology of the TREM cluster. Our second approach to understanding the role of TREM in regulation of innate immunity and cancer is dissection of the DAP12 signaling pathway in myeloid cells. Our studies have identified a shifting, developmentally regulated signaling cassette in macrophages and monocytes. Monocytes express two key intracellular adaptor proteins, the Linker for Activation of T cells (LAT) and the Linker for Activation of B cells (LAB, also known as the Non-T cell Adaptor, NTAL). We find that during maturation of DC or macrophages from monocytes in vitro, the levels of LAT fall whereas the levels of LAB increase. Our previous work had demonstrated the ability of LAB to regulate inflammatory cytokine production in macrophages. More recently, we have demonstrated that dendritic cells (DC) signal via LAB. A screen of multiple DC lignads suggested that the fungal particle zymosan (Zy) could elicit robust LAB phosphorylation whereas TLR stimulation does not. Fractionation and transfection studies demonstrated that LAB phosphorylation was caused by fungal-derived mannons signaling via Dectin-1 on the DC cell surface. Interestingly, we found that DC lacking LAB produced lower levels of inflammatory cytokine due to increased levels of nuclear beta catenin. Accordingly, T cell responses are reduced in LAB null mice and these mice are more susceptible to fungal infection. In addition to our signaling studies in the myeloid compartment of the innate immune system we study the role of the TREM in the inflammation associated with cancer. We find that tumor associated myeloid-derived suppressor cells express TREM1 and that mice harboring 4T1 breast cancers have elevated levels of soluble (s)TREM1 in their blood. In addition, we find high expression of TREM2 on tumor associated macrophages and we have demonstrated the involvement of TREM-2 on colitis and colon cancer associated with colitis. Most recently we have been involved in the characterization of TREM-like Transcript-4 (Treml4) in cardiovascular disease. This work has defined Treml4 as an unusual protein that is highly expressed in neutrophils. Polymorphisms within Treml4 are associated with expression and correlate with cardiovascular disease.

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National Cancer Institute Division of Basic Sciences
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Sen, Shurjo K; Boelte, Kimberly C; Barb, Jennifer J et al. (2014) Integrative DNA, RNA, and protein evidence connects TREML4 to coronary artery calcification. Am J Hum Genet 95:66-76
Orr, Selinda J; Burg, Ashley R; Chan, Tim et al. (2013) LAB/NTAL facilitates fungal/PAMP-induced IL-12 and IFN-? production by repressing ?-catenin activation in dendritic cells. PLoS Pathog 9:e1003357
Montalvo, Vanessa; Quigley, Laura; Vistica, Barbara P et al. (2013) Environmental Factors Determine DAP12 Deficiency To Either Enhance or Suppress Immunopathogenic Processes. Immunology :
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McVicar, Daniel W; Trinchieri, Giorgio (2009) CSF-1R, DAP12 and beta-catenin: a menage a trois. Nat Immunol 10:681-3
Tai, Lee-Hwa; Goulet, Marie-Line; Belanger, Simon et al. (2008) Positive regulation of plasmacytoid dendritic cell function via Ly49Q recognition of class I MHC. J Exp Med 205:3187-99
Yamada, Eriko; McVicar, Daniel W (2008) Paired receptor systems of the innate immune system. Curr Protoc Immunol Chapter 1:Appendix 1X
Whittaker, Gillian C; Burshtyn, Deborah N; Orr, Selinda J et al. (2008) Analysis of the linker for activation of T cells and the linker for activation of B cells in natural killer cells reveals a novel signaling cassette, dual usage in ITAM signaling, and influence on development of the Ly49 repertoire. Blood 112:2869-77
Nurden, Alan T; Nurden, Paquita; Bermejo, Emilse et al. (2008) Phenotypic heterogeneity in the Gray platelet syndrome extends to the expression of TREM family member, TLT-1. Thromb Haemost 100:45-51

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