Cloning and characterization of a novel mouse myeloid DAP12-associated receptor family

The presence of a negatively charged residue in the transmembrane domain of DAP12 precludes its cell surface expression in the absence of a partner re ceptor containing a positive charge in its transmembrane domain. We utilize d this property of DAP12 to screen a BALB/c macrophage cDNA library for nov el molecules that induce cell surface expression of DAP12. By this method, we cloned a cell surface receptor with a single Ig M domain, a transmembran e lysine residue, and a short cytoplasmic domain. By homology screening of BALB/c macrophage libraries, we identified a second cDNA for a highly homol ogous receptor. These receptors appear to be the mouse orthologues of a rec ently identified human cDNA, TREM-2, so we have designated the receptors as mouse TREM-2a and TREM-2b. By Northern blotting, transcripts for TREM-2 we re found in each of three macrophage cell lines but not in a variety of oth er hematopoietic cell lines. We further demonstrate that TREM-2a is associa ted with endogenous DAP12 in macrophage cells, and cross-linking of TREM-2a on the surface of macrophages leads to the release of nitric oxide. Our st udies define TREM-2 as a receptor family in mouse macrophages and demonstra te the capacity of these receptors to activate macrophage function through DAP12.