Mycobacterium tuberculosis suppresses protective Th17 responses during infection

Mycobacterium tuberculosis (Mtb) causes more deaths annually than any other pathogen, yet an effective vaccine remains elusive. IFN-γ-producing Th1 CD4+ T cells are necessary but insufficient for protection against infection. In humans, the development of IL-17A-producing Th17 T cells correlates with protection; however, not all individuals develop a Th17 response. In mice, experimental vaccines can elicit protective Th17 cells, yet Th17s are rare in primary infection. Why Mtb fails to consistently elicit Th17s is unknown. Here, we identify factors suppressing Th17 responses during primary infection. We demonstrate that the lack of Th17 induction is independent of route and duration. Next, using Tbx21-deficient mice, we show that Mtb drives a Th1 response that is only partially protective and limits Th17 cell production in an IFN-γ-independent manner. We further reveal that the ESX-1 type VII secretion system and lipid phthiocerol dimycocerosate (PDIM) suppress Th17 responses. Infection with ESX-1 or PDIM mutants results in significantly increased Th17 T cells and IL-17A cytokine in the lungs, and infection of IL-17A-deficient animals partially restores virulence of ESX-1 and PDIM mutants. Although the ESX-1 secretion system and lipid PDIM elicit type I IFN, which can suppress Th17 differentiation, we find that suppression of Th17 is independent of type I IFN. Instead, ESX-1 and PDIM suppress production of IL-23, a cytokine that promotes Th17 differentiation, in dendritic cells found in mediastinal lymph nodes during Mtb infection. These findings define a new function of the ESX-1 secretion system and PDIM in Mtb virulence, a long-standing question in tuberculosis research.