Neutrophil subsets play dual roles in tuberculosis by producing inflammasome dependent-IL-1β or suppressing T-cells via PD-L1

Doz-Deblauwe, E.; Bounab, B.; Carreras, F.; Silverira-Fahel, J.; Oliveira, S. C.; Lamkanfi, M.; Le Vern, Y.; GERMON, P.; Pichon, J.; Kempf, F.; Paget, C.; Remot, A.; Winter, N.

doi:10.1101/2023.11.17.567521

bioRxiv · 10.1101/2023.11.17.567521

Neutrophil subsets play dual roles in tuberculosis by producing inflammasome dependent-IL-1β or suppressing T-cells via PD-L1

Doz-Deblauwe, E.·Bounab, B.·Carreras, F.·Silverira-Fahel, J.·Oliveira, S. C.·Lamkanfi, M.·Le Vern, Y.·GERMON, P.·Pichon, J.·Kempf, F.·Paget, C.·Remot, A.·Winter, N.

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Abstract

Neutrophils can be beneficial or deleterious during tuberculosis (TB). Based on the expression of MHC-II and programmed death ligand 1 (PD-L1), we distinguished two functionally and transcriptionally distinct neutrophil subsets in the lungs of mice infected with mycobacteria. Inflammatory [MHC-II-, PD-L1lo] neutrophils produced inflammasome-dependent IL-1{beta} in the lungs in response to virulent mycobacteria and "accelerated" deleterious inflammation, which was highly exacerbated in IFN-{gamma}R-/- mice. Regulatory [MHC-II+, PD-L1hi] neutrophils "brake" inflammation by suppressing T-cell proliferation and IFN-{gamma} production. Such beneficial regulation, which depends on PD-L1, is controlled by IFN-{gamma}R signaling in neutrophils. The hypervirulent HN878 strain from the Beijing genotype curbed PD-L1 expression by regulatory neutrophils, abolishing the braking function and driving deleterious hyper-inflammation in the lungs. These findings add a layer of complexity to the roles played by neutrophils in TB and may explain the reactivation of this disease observed in cancer patients treated with anti-PD-L1. One Sentence SummaryRegulatory and inflammatory neutrophil subsets play inverse roles in tuberculosis.

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Doz-Deblauwe, E., Bounab, B., Carreras, F., Silverira-Fahel, J., Oliveira, S. C., Lamkanfi, M., Le Vern, Y., GERMON, P., Pichon, J., Kempf, F., Paget, C., Remot, A., Winter, N.. 2023-11-17. Neutrophil subsets play dual roles in tuberculosis by producing inflammasome dependent-IL-1β or suppressing T-cells via PD-L1. https://doi.org/10.1101/2023.11.17.567521

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