Hematopoietic dysregulation caused by neutrophils underlies impaired T-cell response and enhanced susceptibility to tuberculosis.

Abstract Control of Mycobacterium tuberculosis (Mtb) infection requires the generation of T cells that migrate to granulomas, specialized immune structures surrounding sites of bacterial replication. Here we report that persistent influx of neutrophils impedes T-cell recruitment to the lung and limits bacterial control in tuberculosis (TB) granulomas. We found that type I interferons (IFN-1) induced by Mtb infection dampens T-cell production in the bone marrow by driving a granulocyte-biased hematopoietic program. Neutrophil-intrinsic IFN-1 signaling, and bacterial type VII secretion system are critical for this process. Mechanistically, we demonstrate that IFN-1 facilitates neutrophil influx to the lung, where these cells produce granulocyte colony stimulating factor (G-CSF) in response to Mtb and neutrophil extracellular traps (NETs). Augmented and sustained release of G-CSF support granulopoiesis and impair lymphopoiesis, causing sub-optimal T-cell responses in the lung and spleen. Therapeutically, inhibiting IFN-1 signaling or neutralizing G-CSF limits neutrophil-driven immunopathology and bacterial replication by restoring optimal T-cell responses. Thus, we identify a mechanism by which neutrophils limit T-cell immunity during TB by disrupting the hematopoietic equillibrium and propose “IFN-1→NETosis→GCSF” immune axis as targets for host-directed therapy and immunization