DAP12 modulates pro-inflammatory cytokine responses to M.tb infection. Groups of
WT and DAP12 KO mice were sacrificed at either d7 or d14 or d21 post-infection. The
protein levels of IFNγ (A) and IL-12 (B) were measured in the lung homogenates by
ELISA. Results are expressed as mean±SEM of cytokine levels from three mice per
group, representative of two independent experiments.
DAP12 modulates TNF-α production by APC and Th1 cells upon M.tb infection.
Lung cells were isolated from WT and DAP12 KO mice at d14 post-infection and subject
to immunostaining and ICS. Data are expressed as mean±SEM of total numbers per lung
of TNF-α-producing APC (CD11chiCD11bmed, CD11cmedCD11bhi, and CD11cCD11bmed) and CD4 T cells from four mice/group.
DAP12 modulates innate immune cell responses in the lung in response to M.tb
infection. Lung mononuclear cells from groups of WT and DAP12 KO mice sacrificed at
7 days post-infection were analyzed by flow cytometry. Absolute numbers of different
types of innate cells are expressed as mean±SEM from three mice per group,
representative of two independent experiments.
Suppl. Figure 4
Schematic illustration of the mechanistic model where mycobacterial pathogens
employ the DAP12-IRAK-M-IL-10 pathway in APC to delay and reduce Th1
immunity in the lung. Mycobacterial ligands recognized by DAP12 associated nonsignaling receptors TREM-1, TREM-2 and MDL-1 signal through transmembrane
immunoadaptor DAP12 to induce TLR-negative regulator IRAK-M in APC. IRAK-M
also induces anti-inflammatory cytokine IL-10, which in turn inhibits pro-inflammatory
cytokine and chemokine production in APC and T cell activation. On the other hand,
IRAK-M inhibits IRAK-4 phosphorylation of IRAK-1, dampening NFκB activation and
nuclear translocation which further inhibits APC activation. Functionally suppressed
APC become defective in their ability to present antigen and to activate antigen-reactive
Th1 cells in the draining lymph nodes. These events lead to a significant delay in the
recruitment of antigen-reactive Th1 cells to the lung and reduced protection.