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Review
, 19 (4), 441-7

Interleukin-12 and Tuberculosis: An Old Story Revisited

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Review

Interleukin-12 and Tuberculosis: An Old Story Revisited

Andrea M Cooper et al. Curr Opin Immunol.

Abstract

Our understanding of the role of interleukin (IL)-12 in controlling tuberculosis has expanded because of increased interest in other members of the IL-12 family of cytokines. Recent data show that IL-12, IL-23 and IL-27 have specific roles in the initiation, expansion and control of the cellular response to tuberculosis. Specifically, IL-12, and to a lesser degree IL-23, generates protective cellular responses and promotes survival, whereas IL-27 moderates the inflammatory response and is required for long-term survival. Paradoxically, IL-27 also limits bacterial control, suggesting that a balance between bacterial killing and tissue damage is required for survival. Understanding the balance between IL-12, IL-23 and IL-27 is crucial to the development of immune intervention in tuberculosis.

Figures

Figure 1
Figure 1. IL-12 family cytokines in cellular response to M.tuberculosis infection
Macrophages and DCs are exposed to M. tuberculosis following aerosol infection of the lung. M. tuberculosis activated lung DCs produce IL-12p40, become responsive to the chemokines CCL19 and CCL21 and carry the antigen from the lung to the draining lymph node. IL-23 produced by activated DCs during the DC-T cell interaction promotes proliferation of antigen-specific CD4 T cells. IL-12 (and to a lesser extent IL-27 and IL-23) produced by activated DCs promotes polarization of naïve CD4 T cells into a Th1 phenotype while TGF-β and IL-6 promote polarization of Th17 cells. Both Th1 and Th17 cells migrate and populate the lung compartment in response to inflammation-induced chemokine gradients. The arrival of the IFN-γ producing Th1 cells correlates with the activation of infected macrophages in the lung and bacterial control. The absence of the IL-17 producing Th17 cells does not impact bacterial burden but does alter granuloma formation. γδ T cells also produce IL-17 in the lung of mycobacterially-infected mice.
Figure 2
Figure 2. Regulation of cellular responses by IL-12 cytokine family members during M.tuberculosis infection
During chronic tuberculosis, IL-12 is required for the long-term maintenance of Th1 CD4 T cells in the lung, while IL-23 is required for the persistence and maintenance Th17 cells and IL-17. IFN-γ produced by Th1 cells negatively regulates Th17 while IL-27 promotes production of IFN-γ by Th1 cells and limits inflammation. Lipoxin negatively regulates IL-12 production during infection and may limit the inflammatory response in chronic disease. IL-23/IL-17 from Th17 and/or γδ T cells modulates the inflammatory response possibly by recruitment of neutrophils.

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