IL-22 produced by type 3 innate lymphoid cells (ILC3s) reduces the mortality of type 2 diabetes mellitus (T2DM) mice infected with Mycobacterium tuberculosis.

Author summary Type 2 diabetes mellitus (T2DM) during Mtb-infection leads to a pathological immune response in the lung. IL-22 plays an important role in the host defense against bacteria at mucosal surfaces, maintaining tissue barrier integrity by protecting epithelial cells and reducing chronic inflammation. In the current study, we investigated the role of IL-22 during Mtb infection in human samples and T2DM mice. We found that plasma IL-22 levels were significantly lower in Mtb-infected T2DM mice than in Mtb-infected nondiabetic mice. Similarly, IL-22 levels were significantly lower in TB patients with T2DM than in TB patients without T2DM. Type 3 innate lymphoid cells (ILC3s) were an important source of IL-22 in the lungs of Mtb-infected mice. Mtb-infected T2DM mouse lungs had fewer IL-22+ ILC3s than did the lungs of Mtb-infected non-T2DM mice. Recombinant IL-22 and IL-22 producing ILC3s reduced the bacterial burden, lung epithelial cell damage, insulin level and lipid metabolites and prolonged the survival of Mtb-infected T2DM mice. Our findings demonstrate that IL-22 produced by ILC3s is essential to inhibit excess inflammation and epithelial cell damage in T2DM mice infected with Mtb. Further understanding of these mechanisms and human studies can help to treat TB patients with T2DM. Previously, we found that pathological immune responses enhance the mortality rate of Mycobacterium tuberculosis (Mtb)-infected mice with type 2 diabetes mellitus (T2DM). In the current study, we evaluated the role of the cytokine IL-22 (known to play a protective role in bacterial infections) and type 3 innate lymphoid cells (ILC3s) in regulating inflammation and mortality in Mtb-infected T2DM mice. IL-22 levels were significantly lower in Mtb-infected T2DM mice than in nondiabetic Mtb-infected mice. Similarly, serum IL-22 levels were significantly lower in tuberculosis (TB) patients with T2DM than in TB patients without T2DM. ILC3s were an important source of IL-22 in mice infected with Mtb, and recombinant IL-22 treatment or adoptive transfer of ILC3s prolonged the survival of Mtb-infected T2DM mice. Recombinant IL-22 treatment reduced serum insulin levels and improved lipid metabolism. Recombinant IL-22 treatment or ILC3 transfer prevented neutrophil accumulation near alveoli, inhibited neutrophil elastase 2 (ELA2) production and prevented epithelial cell damage, identifying a novel mechanism for IL-22 and ILC3-mediated inhibition of inflammation in T2DM mice infected with an intracellular pathogen. Our findings suggest that the IL-22 pathway may be a novel target for therapeutic intervention in T2DM patients with active TB disease.