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 begun to assess the role that TREM2 may play in inflammation associated cancer of the colon.
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