Triggering receptor expressed on myeloid cells 2 (TREM-2) is a modulator of pattern recognition receptors on innate immune cells that regulates the inflammatory response. However, the role of TREM-2 in in vivo models of infection and inflammation remains controversial. Here, we demonstrated that TREM-2 expression on CD4+ T cells was induced by Mycobacterium tuberculosis infection in both humans and mice and positively associated with T cell activation and an effector memory phenotype. Activation of TREM-2 in CD4+ T cells was dependent on interaction with the putative TREM-2 ligand expressed on DCs. Unlike the observation in myeloid cells that TREM-2 signals through DAP12, in CD4+ T cells, TREM-2 interacted with the CD3ζ-ZAP70 complex as well as with the IFN-γ receptor, leading to STAT1/-4 activation and T-bet transcription. In addition, an infection model using reconstituted Rag2–/– mice (with TREM-2–KO vs. WT cells or TREM-2+ vs. TREM-2–CD4+ T cells) or CD4+ T cell–specific TREM-2 conditional KO mice demonstrated that TREM-2 promoted a Th1-mediated host defense against M. tuberculosis infection. Taken together, these findings reveal a critical role of TREM-2 in evoking proinflammatory Th1 responses that may provide potential therapeutic targets for infectious and inflammatory diseases.
Yongjian Wu, Minhao Wu, Siqi Ming, Xiaoxia Zhan, Shengfeng Hu, Xingyu Li, Huan Yin, Can Cao, Jiao Liu, Jinai Li, Zhilong Wu, Jie Zhou, Lei Liu, Sitang Gong, Duanman He, Xi Huang