Harmful Effects of Granulocytic Myeloid-Derived Suppressor Cells on Tuberculosis Caused by Hypervirulent Mycobacteria

Background. The role of myeloid-derived suppressor cells (MDSCs) in patients with severe tuberculosis who suffer from uncontrolled pulmonary inflammation caused by hypervirulent mycobacterial infection remains unclear. Methods. This issue was addressed using C57BL/6 mice infected with highly virulent Mycobacterium bovis strain MP287/03. Results. CD11b(+)GR1(int) population increased in the bone marrow, blood and lungs during advanced disease. Pulmonary CD11b(+)GR1(int) (Ly(6)G(int)Ly6C(int)) cells showed granularity similar to neutrophils and expressed immature myeloid cell markers. These immature neutrophils harbored intracellular bacilli and were preferentially located in the alveoli. T-cell suppression occurred concomitantly with CD11b(+)GR1(int) cell accumulation in the lungs. Furthermore, lung and bone marrow GR1(+) cells suppressed both T-cell proliferation and interferon gamma production in vitro. Anti-GR1 therapy given when MDSCs infiltrated the lungs prevented expansion and fusion of primary pulmonary lesions and the development of intragranulomatous caseous necrosis, along with increased mouse survival and partial recovery of T-cell function. Lung bacterial load was reduced by anti-GR1 treatment, but mycobacteria released from the depleted cells proliferated extracellularly in the alveoli, forming cords and clumps. Conclusions. Granulocytic MDSCs massively infiltrate the lungs during infection with hypervirulent mycobacteria, promoting bacterial growth and the development of inflammatory and necrotic lesions, and are promising targets for host-directed therapies. (AU)