Human IL-23-Producing Type 1 Macrophages Promote but IL-10-Producing Type 2 Macrophages Subvert Immunity to (Myco)Bacteria

Macrophages (Mφ) play a central role as effector cells in immunity to intracellular pathogens such as Mycobacterium. Paradoxically, they also provide a habitat for intracellular bacterial survival. This paradoxical role of Mφ remains poorly understood. Here we report that this dual role may emanate from the functional plasticity of Mφ: Whereas Mφ-1 polarized in the presence of granulocyte-Mφ colony-stimulating factor promoted type 1 immunity, Mφ-2 polarized with Mφ colony-stimulating factor subverted type 1 immunity and thus may promote immune escape and chronic infection. Importantly, Mφ-1 secreted high levels of IL-23 (p40/p19) but no IL-12 (p40/p35) after (myco)bacterial activation. In contrast, activated Mφ-2 produced neither IL-23 nor IL-12 but predominantly secreted IL-10. Mφ-1 required IFN-γ as a secondary signal to induce IL-12p35 gene transcription and IL-12 secretion. Activated dendritic cells produced both IL-12 and IL-23, but unlike Mφ-1 they slightly reduced their IL-23 secretion after addition of IFN-γ. Binding, uptake, and outgrowth of a mycobacterial reporter strain was supported by both Mφ subsets, but more efficiently by Mφ-2 than Mφ-1. Whereas Mφ-1 efficiently stimulated type 1 helper cells, Mφ-2 only poorly supported type 1 helper function. Accordingly, activated Mφ-2 but not Mφ-1 down-modulated their antigen-presenting and costimulatory molecules (HLA-DR, CD86, and CD40). These findings indicate that (i) Mφ-1 and Mφ-2 play opposing roles in cellular immunity and (ii) IL-23 rather than IL-12 is the primary type 1 cytokine produced by activated proinflammatory Mφ-1. Mφ heterogeneity thus may be an important determinant of immunity and disease outcome in intracellular bacterial infection.