Tissue-resident-like CD4+ T cells secreting IL-17 control Mycobacterium tuberculosis in the human lung

Abstract

T cell immunity is essential for the control of tuberculosis (TB), an important disease of the lung, and is generally studied in humans using peripheral blood cells. Mounting evidence, however, indicates that tissue resident memory T cells (Trm) are superior at controlling many pathogens, including Mycobacterium tuberculosis (Mtb), and can be quite different from those in circulation. Using freshly resected lung tissue, from individuals with active or previous TB, we identified distinct CD4 and CD8 Trm-like clusters within TB diseased lung tissue that were functional and enriched for IL-17 producing cells. Mtb-specific CD4 T cells producing TNF-α, IL-2 and IL-17 were highly expanded in the lung compared to matched blood samples, in which IL-17+ cells were largely absent. Strikingly, the frequency of Mtb-specific lung T cells making IL-17, but not other cytokines, inversely correlated with the plasma IL-1β levels, suggesting a potential link with disease severity. Using a human granuloma model, we showed the addition of either exogenous IL-17 or IL-2 enhanced immune control of Mtb and was associated with increased NO production. Taken together, these data support an important role for Mtb-specific Trm-like IL-17 producing cells in the immune control of Mtb in the human lung.

Precision Vaccine Development: Cues From Natural Immunity

“…Activated and exhausted TRMs were found to be predominant at infection sites in TB patients ( 65 ). A very recent study identified the protective role of IL-17 producing TRM cell clusters in MTB infected human lungs ( 66 ). Further in vivo observations and correlates of protection to identify which immunological response(s) are essential are needed before development of new vaccines against MTB.…”

Co-Ordination of Mucosal B Cell and CD8 T Cell Memory by Tissue-Resident CD4 Helper T Cells

“…Both circulating T H 17 memory cells and T H 17 T RM cells are important to clear the C. albicans upon rechallenge, but T H 17 T RM cells are more effective in rapidly clearing the pathogens [87]. In Mycobacterium tuberculosis (M. tuberculosis)-infected patients, lung CD4 T RM cells produce IL-17 following antigenic stimulation, which along with IL-17 and IL-2 produced by T H 17 T RM cells suppress the growth of M. tuberculosis in 3D culture system [88].…”

Advancing Adjuvants for Mycobacterium tuberculosis Therapeutics

“…Furthermore, both CD4 + and CD8 + human T RM cells have been characterised as capable of limiting intracellular Mtb survival ex vivo ( 70 ). A recent study using human samples also found that the frequency of Mtb-specific T RM -like cells that produce IL-17 in the lungs negatively correlated with IL-1ß levels in the blood, suggesting an important role for controlling Mtb growth ( 71 ). Additionally, mucosal vaccination could help activate other resident cells, such as γδ-T cells and mucosal-associated invariant T cells (MAIT), that also produce IL-17A ( 53 ).…”