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. 2017 Apr 5;8:294. doi: 10.3389/fimmu.2017.00294

Figure 3.

Figure 3

Hypothetical interplay between type I interferons (T1-IFNs) and IFN-γ in monocyte priming and shaping of the immune response in Mtb infection. Dashed lines indicate speculations in the context of pulmonary Mtb infection; solid lines indicate shown pathways in human and/or in animal models. (1) T1-IFN induces migration of CCR2+ monocytes (iMo) from the bone marrow to the lungs of Mtb-infected mice under influence of CCL2 (72). Locally, these cells develop into CD11b+Ly6Chigh inflammatory macrophages (iM) and CD11b+Ly6Cint inflammatory dendritic cells (iDC) (43). (2) As shown in Figure 1, naïve iM and iDC can initiate either IL-1β-mediated inflammation or T1-IFN-mediated inflammation. Mtb actively triggers intracellular pattern recognition receptors to induce a T1-IFN-mediated response. (3) Additionally, iM and iDC in the naïve situation have differentiated under influence of M-CSF, which makes them more responsive to T1-IFN signaling (94). During progression of Mtb infection, GM-CSF levels rise and increase the potential for IL-1β production by iM and iDC (94, 125, 155, 156). (4) Similar to the situation in gut infection, we propose that in tuberculosis (TB) IL-12 production in the lungs stimulates IFN-γ production by bone-marrow-resident NK cells, which locally primes monocytes (154). IFN-γ priming of monocyte-derived iDC is necessary for T1-IFNs to induce a regulatory (iregDC) phenotype in iDC in the lungs (43). (5) Additionally, IFN-γ stimulates monopoiesis over granulopoiesis by granulocyte/macrophage progenitor cells (128). (6) As Mtb infection progresses and GM-CSF levels increase, iM and iDC readily produce IL-1β [see also (3)] (124, 155), which can lead to PMN-mediated inflammatory damage in TB (120). (7) IL-1β production can be inhibited in response to either IFN-γ or IFN-β through mechanistically distinct pathways that differently affect Mtb killing. (8) Signaling through IFN-α/β receptor in IFN-γ-primed iDCs induces IL-10 production (43, 115, 131), inhibits IL-12 production (115), and makes these cells unresponsive to activation by IFN-γ (43, 115, 141), which together interfere with protective immunity during acute Mtb infection.