IL-17A-producing γδ T cells control pulmonary Mycobacterium abscessus infection in mice.

The specific role of γδ T cells in non-tuberculous mycobacteria (NTM) infections remains incompletely understood. Here we characterized the immune landscape of pulmonary tissues from a Mycobacterium abscessus-infected NTM mice model. Interleukin-17 (IL-17)A+ γδ T cells were essential for controlling M. abscessus infection by directly eliminating extracellular bacteria. These cells conferred protective immunity in two mouse models of infection combined with either pulmonary fibrosis or a lack of functional interferon-gamma (IFNγ)-mediated immunity. IL-17A+ γδ T cells exerted bactericidal activity via granzyme B-dependent cytotoxic pathways. Absence of IL-17A substantially impaired bacterial recognition and cytotoxic function of IL-17A+ γδ T cells, highlighting the cell-intrinsic requirement for IL-17A signalling in γδ T cell activation. M. abscessus recognition through Toll-like receptor 2 induced macrophage production of IL-1β and IL-23, promoting the expansion and activation of IL-17A+ γδ T cells. Single-cell RNA sequencing on human peripheral blood mononuclear cells suggests that anti-IFNγ autoantibodies compromise γδ T cell function. Our findings establish IL-17A+ γδ T cells as a promising therapeutic target for NTM infections, particularly when IFNγ-dependent immunity is compromised.