[S9-4] Mycobacteria evade host immunity via TREM2, a macrophage receptor for non-glycosylated mycolic acids
Mycobacterial cell-wall glycolipids elicit an anti-mycobacterial macrophage activation via FcRγ-associated C-type lectin receptors (CLRs) including Mincle, a receptor for the cord factor TDM, and downstream signaling through CARD9. Whereas, mycobacterial cell-wall also contains immune-modulatory lipids associated with virulence and latency; however, their mechanism of action remains unclear. Here, we show that TREM2, a DAP12-associated innate immune receptor expressed on macrophages, recognizes non-glycosylated mycolic acids (MA) in mycobacterial cell-walls. Glycosylated MA-containing lipids, such as TDM and GMM, induces anti-mycobacterial M1-type macrophages that produce the macrophage chemoattractant MCP-1, the inflammatory cytokine TNF, and nitric oxide (NO), in a Mincle/FcRγ/CARD9-dependent manner. Conversely, non-glycosylated MAs, such as free MA and GroMM, induces maycobacterium-permissive macrophages that produce only MCP-1 but not TNF and NO, in a TREM2/DAP12-dependent but CARD9-independent manner. Furthermore, TREM2 deletion enhances Mincle-induced macrophage activation in vitro and inflammation in vivo and accelerates the elimination of mycobacterial infection in lungs, suggesting that TREM2 counteracts Mincle/CARD9-mediated anti-mycobacterial immunity. Mycobacteria, therefore, harness TREM2 for immune evasion.