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Verreck, F.A. et al.

Verreck, de Boer, Langenberg, Hoeve, Kramer, Vaisberg, Kastelein, Kolk, de Waal-Malefyt, Ottenhoff,

Human IL-23- producing type 1 macrophages promote but IL-10-producing type 2 macrophages subvert immunity to (myco)bacteria.

Macrophages (Mphi) 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 Mphi remains poorly understood. Here we report that this dual role may emanate from the functional plasticity of Mphi: Whereas Mphi-1 polarized in the presence of granulocyte-Mphi colony-stimulating factor promoted type 1 immunity, Mphi-2 polarized with Mphi colony-stimulating factor subverted type 1 immunity and thus may promote immune escape and chronic infection. Importantly, Mphi-1 secreted high levels of IL-23 (p40/ p19) but no IL-12 (p40/ p35) after (myco)bacterial activation. In contrast, activated Mphi-2 produced neither IL-23 nor IL-12 but predominantly secreted IL-10. Mphi-1 required IFN-gamma 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 Mphi-1 they slightly reduced their IL-23 secretion after addition of IFN-gamma. Binding, uptake, and outgrowth of a mycobacterial reporter strain was supported by both Mphi subsets, but more efficiently by Mphi-2 than Mphi-1. Whereas Mphi-1 efficiently stimulated type 1 helper cells, Mphi-2 only poorly supported type 1 helper function. Accordingly, activated Mphi-2 but not Mphi-1 down-modulated their antigen-presenting and costimulatory molecules (HLA-DR, CD86, and CD40). These findings indicate that (i) Mphi-1 and Mphi-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 Mphi-1. Mphi heterogeneity thus may be an important determinant of immunity and disease outcome in intracellular bacterial infection.[1]

References

Human IL-23-producing type 1 macrophages promote but IL-10-producing type 2 macrophages subvert immunity to (myco)bacteria. Verreck, F.A., de Boer, T., Langenberg, D.M., Hoeve, M.A., Kramer, M., Vaisberg, E., Kastelein, R., Kolk, A., de Waal-Malefyt, R., Ottenhoff, T.H. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]

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