Ly6G ⁺ Granulocytes-derived IL-17 limits protective host responses and promotes tuberculosis pathogenesis

The protective correlates of Mycobacterium tuberculosis ( Mtb ) infection-elicited host immune responses are incompletely understood. Here, we report pro-pathogenic crosstalk involving Ly6G ⁺ granulocytes (Ly6G ⁺ Gra), IL-17 and COX2. We show that in the lungs of Mtb -infected wildtype mice, either BCG-vaccinated or not, most intracellular bacilli are Ly6G ⁺ Gra-resident four weeks post-infection onwards. In the genetically susceptible IFNψ ^-/- mice, excessive Ly6G ⁺ Gra infiltration correlates with severe bacteraemia. Neutralizing IL-17 (anti-IL17mAb) and COX2 inhibition by celecoxib reverse Ly6G ⁺ Gra infiltration, associated pathology and death in IFNψ ^-/- mice. Surprisingly, Ly6G ⁺ Gra also serves as the major source of IL-17 in the lungs of Mtb -infected WT or IFNψ ^-/- mice. The IL-17-COX2-Ly6G ⁺ Gra interplay also operates in WT mice. Inhibiting RORψt, the key transcription factor for IL-17 production or COX2, reduces the bacterial burden in Ly6G ⁺ Gra, leading to reduced bacterial burden and pathology in the lungs of WT mice. In the Mtb -infected WT mice, COX2 inhibition abrogates IL-17 levels in the lung homogenates and significantly enhances BCG’s protective efficacy, mainly by targeting the Ly6G ⁺ Gra-resident Mtb pool, a phenotype also observed when IL-17 is blocked by RORψt inhibitor. Furthermore, in pulmonary TB patients, high neutrophil count and IL-17 correlated with adverse treatment outcomes. Together, our results suggest that IL-17 and PGE2 are the negative correlates of protection, and we propose targeting the pro-pathogenic IL-17-COX2-Ly6G ⁺ Gra axis for TB prevention and therapy.