The role of Th17 cells in host defense against intracellular bacterial infection
Human host defense against mycobacteria depends on a functioning immune system. While it is currently established that Th1 cells are major players in host defense against mycobacteria, other cell types such as Th17 cells also correlate strongly with the protective forms of disease. However, the role of Th17 cells in the context of intracellular infection are incompletely understood. Recent work has shown that Th17 cells can secrete an antimicrobial protein IL-26, which can directly lyse extracellular bacteria. Given the established role of antimicrobial peptides against mycobacterial infection, we decided to further investigate IL-26 and determine whether it is antimicrobial against mycobacteria. We find that IL-26 can be secreted by PBMCs and purified T cells in response to IL-1β in the absence of T cell receptor activation. This process is also more rapid than TCR stimulation. Among helper T cells, we show that IL-1RI expression was necessary for this response and identified IL-1RI+ Th17 cells as a cell type that can secrete IL-26 in response to IL-1β. Furthermore, we establish that IL-26 secreted in response to IL-1β is functionally antimicrobial.
We also examined whether IL-26 is antimicrobial against intracellular bacteria. We find that IL-26 is differentially expressed between clinical forms of leprosy, with higher expression in tuberculoid leprosy, the resistant form of the disease, as compared to lepromatous leprosy, the progressive form of the disease. Incubation of IL-26 with M. leprae and attenuated M. tuberculosis strain H37RA led to dose dependent killing, both with bacteria in culture and, importantly, while the bacteria resided within infected macrophages. Additionally, we find that IL-26 treatment of infected macrophages stimulates the autophagy response and enhances phagolysosome fusion in a STING dependent manner. Altogether, this work uncovers a novel mechanism by which Th17 cells contribute to defense against mycobacterial infection.