Monocytic myeloid-derived suppressor cells reflect tuberculosis severity and are influenced by cyclooxygenase-2 inhibitors

Abstract

Myeloid-derived suppressor cells (MDSCs) increase in tuberculosis (TB) and may be targets for host-directed therapy (HDT). In this study, we use flow cytometry to analyze the effects of cyclooxygenase-2 inhibitors (COX-2i) on monocytic (M)-MDSCs in blood from TB patients attending a clinical trial of COX-2i. The effects of COX-2i on M-MDSCs and mycobacterial uptake were also studied by an in vitro mycobacterial infection model. We found that M-MDSC frequencies correlated with TB disease severity. Reduced M-MDSC (P = 0.05) and IDO (P = 0.03) expression was observed in the COX-2i group. We show that peripheral blood-derived M-MDSCs successfully internalized Mycobacterium bovis and that in vitro mycobacterial infection increased COX-2

Myeloid-Derived Suppressor Cells Mediate T Cell Dysfunction in Nonhuman Primate TB Granulomas

“…Our study demonstrates that ATB is characterized by a measurable increase in MDSC levels in both peripheral blood and BAL fluid, with significant recruitment of these cells to the outer periphery of the granulomas. Our results raise the possibility that MDSCs can serve as a promising biomarker for ATB, while their disappearance could correlate with successful therapy ( 7 – 9 , 11 , 30 , 33 ). Furthermore, they may serve as a potential target for adjunctive TB therapeutics ( 9 , 11 , 25 , 30 , 32 , 35 , 36 , 41 ), helping to resolve the granulomatous TB niche and consequently the potential for reactivation from latent TB to ATB.…”

“…MDSCs from both intratumoral regions and peripheral circulation induce similar immunosuppressive capabilities, and their recruitment has been suggestive of severity and progression of cancer as well as treatment failure ( 22 , 55 ). A number of studies have established a similar increase in MDSC frequencies associated with ATB in murine models ( 10 , 36 ) and human patients ( 7 – 9 , 30 , 33 , 41 ). These studies also observed similar phenotypes and functions of MDSCs in murine ( 10 , 36 ) and human ( 7 – 9 , 30 , 33 , 41 ) ATB.…”

“…Myelopoiesis-promoting growth factors, such as granulocyte colony-stimulating factor (G-CSF) ( 37 , 38 ), macrophage CSF (M-CSF), and granulocyte-macrophage CSF (GMCSF) ( 39 ), act together with inflammatory cytokines to promote MDSC expansion and to prevent their differentiation into terminally differentiated DCs, macrophages, or granulocytes ( 39 ). MDSCs potently suppress the function of both CD4 and CD8 T cells ( 10 , 22 , 25 – 33 , 35 , 36 ). Adoptive transferred MDSCs can induce antigen-specific CD8 T cell tolerance in mice ( 40 ).…”

PMN-MDSC Frequency Discriminates Active Versus Latent Tuberculosis and Could Play a Role in Counteracting the Immune-Mediated Lung Damage in Active Disease

“…Indeed, we found an association between high PMN-MDSC frequency and active TB. Some reports showed a higher frequency of Mo-MDSC during TB ( 7 , 24 , 25 ). Differently, we did not detect Mo-MDSC in our patients.…”

Immune Correlates of Non-Necrotic and Necrotic Granulomas in Pulmonary Tuberculosis: A Pilot Study

“…The role of MDSCs in TB progression is further confirmed by the abundance of MDSCs in mouse strains that are vulnerable to progressive disease, including the NOS2 −/− , C3HeB/FeJ, 129S2 strains, for which the highest levels were observed in immunodeficient (RAG2 −/− ) animals, when compared to TB resistant mice that are devoid of solid/non-necrotic granulomas [32]. Furthermore, the frequency of MDSCs circulating in the blood of TB patients correlates with the disease severity [13,[33][34][35]. While M-MDSCs constitute the significant subset of circulating MDSCs, accounting for 4% to 10% of the peripheral blood mononuclear cell (PBMC) fraction, the PMN-MDSC frequency can account for up to 30% of the total PBMCs of TB patients [13,20].…”