TREM-2 promotes Th1 responses by interacting with the CD3ζ-ZAP70 complex following Mycobacterium tuberculosis infection

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 CD3 zeta-ZAP70 complex as well as with the IFN-gamma 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.

Automated summary

TREM-2 is induced on CD4(+) T cells in response to Mycobacterium tuberculosis infection and plays a critical role in promoting proinflammatory Th1 responses for host defense. The study reveals a potential therapeutic target for infectious and inflammatory diseases by targeting TREM-2.