IL-22: An Underestimated Player in Natural Resistance to Tuberculosis?

Approximately 10% of individuals latently infected with Mycobacterium tuberculosis (Mtb) develop active tuberculosis (TB) during their lifetime. Although it is well recognized that T-helper 1 immune responses are crucial for containing latent TB infection, the full array of host factors conferring protective immunity from TB progression are not completely understood. IL-22 is produced by cells of the innate and adaptive immune system including innate lymphoid cells, and natural killer cells as well as T lymphocytes (Th1, Th17, and Th22) and binds to its cognate receptor, the IL-22R1, which is expressed on non-hematopoietic cells such as lung epithelial cells. However, recent studies suggest that Mtb induces expression of the IL-22R1 on infected macrophages and multiple studies have indicated a protective role of IL-22 in respiratory tract infections. Reduced concentrations of circulating IL-22 in active TB compared to latent TB and decreased percentages of Mtb-specific IL-22 producing T cells in TB patients compared to controls designate this cytokine as a key player in TB immunology. More recently, it has been shown that in type 2 diabetes (T2D) and TB co-morbidity serum IL-22 concentrations are further reduced compared to TB patients without co-morbidities. However, whether a causative link between low IL-22 and increased susceptibility to TB and disease severity of TB exists remains to be established. This review summarizes the contribution of IL-22, a potentially under-appreciated key player in natural resistance to TB, at the interface between the immune response to Mtb and the lung epithelium.