Containment of aerogenic <i>Mycobacterium tuberculosis</i> infection in mice does not require MyD88 adaptor function for TLR2, ‐4 and ‐9

The role of Toll‐like receptors (TLR) and MyD88 for immune responses to Mycobacterium tuberculosis ( Mtb ) infection remains controversial. To address the impact of TLR‐mediated pathogen recognition and MyD88‐dependent signaling events on anti‐mycobacterial host responses, we analyzed the outcome of Mtb infection in TLR2/4/9 triple‐ and MyD88‐deficient mice. After aerosol infection, both TLR2/4/9‐deficient and wild‐type mice expressed pro‐inflammatory cytokines promoting antigen‐specific T cells and the production of IFN‐γ to similar extents. Moreover, TLR2/4/9‐deficient mice expressed IFN‐γ‐dependent inducible nitric oxide synthase and LRG‐47 in infected lungs. MyD88‐deficient mice expressed pro‐inflammatory cytokines and were shown to expand IFN‐γ‐producing antigen‐specific T cells, albeit in a delayed fashion. Only mice that were deficient for MyD88 rapidly succumbed to unrestrained mycobacterial growth, whereas TLR2/4/9‐deficient mice controlled Mtb replication. IFN‐γ‐dependent restriction of mycobacterial growth was severely impaired only in Mtb ‐infected MyD88, but not in TLR2/4/9‐deficient bone marrow‐derived macrophages. Our results demonstrate that after Mtb infection neither TLR2, ‐4, and ‐9, nor MyD88 are required for the induction of adaptive T cell responses. Rather, MyD88, but not TLR2, TLR4 and TLR9, is critical for triggering macrophage effector mechanisms central to anti‐mycobacterial defense.