Mycobacterium tuberculosis suppresses protective Th17 responses during infection through multiple mechanisms.

Mycobacterium tuberculosis (Mtb) causes more deaths annually than any other pathogen, yet an effective vaccine remains elusive. IFN-γ-producing CD4+ T cells are necessary but insufficient for immune protection. Data from humans shows that the development of IL-17a producing Th17 T cells correlates with protection against infection, however not all individuals develop a Th17 response. In mouse models, experimental vaccines can elicit protective Th17 cells, but Th17s are rare in primary infection. Here, we identify factors suppressing Th17 responses during primary Mtb infection. First, using Tbet deficient mice, we demonstrate that Mtb drives a Th1 response that is only partially protective and limits the production of protective Th17 cells in an IFN-γ independent manner. Next, we reveal that the ESX-1 type VII alternative secretion system in Mtb suppresses Th17 responses by inhibiting IL-23 production in dendritic cells. These findings define a new function of the ESX-1 secretion system in Mtb virulence, a long-standing question in tuberculosis research.