Therapies for tuberculosis and AIDS: myeloid-derived suppressor cells in focus

Dorhoi, Anca; Kotze, Leigh A.; Berzofsky, Jay A.; Sui, Yongjun; Gabrilovich, Dmitry I.; Garg, Ankita; Hafner, Richard; Khader, Shabaana A.; Schaible, Ulrich E.; Kaufmann, Stefan H. E.; Walzl, Gerhard; Lutz, Manfred B.; Mahon, Robert N.; Ostrand‐Rosenberg, Suzanne; Bishai, William R.; Plessis, Nelita du

doi:10.1172/jci136288

Cited by 31 publications

(42 citation statements)

References 158 publications

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“…Many studies (more than 5,000 listed in PubMed to date) have implicated these cells in regulating immune responses in pathological conditions, including cancer, chronic infection, sepsis and autoimmunity. Physiological roles for MDSCs have also been described in pregnancy and neonates 2 , 3 . It is now evident that MDSCs contribute to the myeloid cell diversity observed in pathological conditions.…”

Section: Introductionmentioning

confidence: 99%

Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity

2021

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Myeloid-derived suppressor cells (MDSCs) are pathologically activated neutrophils and monocytes with potent immunosuppressive activity. They are implicated in the regulation of immune responses in many pathological conditions and are closely associated with poor clinical outcomes in cancer. Recent studies have indicated key distinctions between MDSCs and classical neutrophils and monocytes, and, in this Review, we discuss new data on the major genomic and metabolic characteristics of MDSCs. We explain how these characteristics shape MDSC function and could facilitate therapeutic targeting of these cells, particularly in cancer and in autoimmune diseases. Additionally, we briefly discuss emerging data on MDSC involvement in pregnancy, neonatal biology and COVID-19.

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Section: Introductionmentioning

confidence: 99%

Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity

2021

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“…In cancer, G-MDSCs are associated with tumor progression and escape to the immune surveillance (36). In chronic infections such as tuberculosis (37,38) or AIDS (39), or acute inflammatory syndrome such as sepsis (40) MDSCs are targeted for new host-directed therapies. However, MDSCs, including regulatory neutrophils, are also beneficial to the host under some circumstances.…”

Section: Discussionmentioning

confidence: 99%

Neutrophils Encompass a Regulatory Subset Suppressing T Cells in Apparently Healthy Cattle and Mice

et al. 2021

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Neutrophils that reside in the bone marrow are swiftly recruited from circulating blood to fight infections. For a long time, these first line defenders were considered as microbe killers. However their role is far more complex as cross talk with T cells or dendritic cells have been described for human or mouse neutrophils. In cattle, these new roles are not documented yet. We identified a new subset of regulatory neutrophils that is present in the mouse bone marrow or circulate in cattle blood under steady state conditions. These regulatory neutrophils that display MHC-II on the surface are morphologically indistinguishable from classical MHC-IIneg neutrophils. However MHC-IIpos and MHC-IIneg neutrophils display distinct transcriptomic profiles. While MHC-IIneg and MHC-IIpos neutrophils display similar bacterial phagocytosis or killing activity, MHC-IIpos only are able to suppress T cell proliferation under contact-dependent mechanisms. Regulatory neutrophils are highly enriched in lymphoid organs as compared to their MHC-IIneg counterparts and in the mouse they express PDL-1, an immune checkpoint involved in T-cell blockade. Our results emphasize neutrophils as true partners of the adaptive immune response, including in domestic species. They open the way for discovery of new biomarkers and therapeutic interventions to better control cattle diseases.

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“…MDSC expand during various pathological conditions as a result of acute or chronic inflammation and are important mediators of immune suppression ( 21 , 23 – 26 , 29 , 31 , 32 , 51 ). In murine TB, MDSC are present at the disease site, harbor mycobacteria, produce cytokines TNF-α, IL-1 α and IL-6, and suppress anti-mycobacterial T-cell IFN-γ responses ( 25 , 33 ).…”

Section: Discussionmentioning

confidence: 99%

Monocytic-Myeloid Derived Suppressor Cells of HIV-Infected Individuals With Viral Suppression Exhibit Suppressed Innate Immunity to Mycobacterium tuberculosis

et al. 2021

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Tuberculosis can occur during any stage of Human Immunodeficiency virus 1 (HIV) -infection including times when CD4+ T cell numbers have reconstituted and viral replication suppressed. We have previously shown that CD11b+CD33+CD14+HLA-DR-/lo monocytic myeloid-derived suppressor cells (MDSC) persist in HIV-infected individuals on combined anti-retroviral therapy (cART) and with virologic suppression. The response of MDSC to Mycobacterium tuberculosis (Mtb) is not known. In this study, we compared the anti-mycobacterial activity of MDSC isolated from HIV –infected individuals on cART with virologic suppression (HIV MDSC) and HIV-uninfected healthy controls (HIV (-) MDSC). Compared to HIV (-) MDSC, HIV MDSC produced significantly less quantities of anti-mycobacterial cytokines IL-12p70 and TNFα, and reactive oxygen species when cultured with infectious Mtb or Mtb antigens. Furthermore, HIV MDSC showed changes in the Toll-like receptor and IL-27 signaling, including reduced expression of MyD88 and higher levels of IL-27. Neutralizing IL-27 and overexpression of MyD88 synergistically controlled intracellular replication of Mtb in HIV MDSC. These results demonstrate that MDSC in fully suppressed HIV-infected individuals are permissive to Mtb and exhibit downregulated anti-mycobacterial innate immune activity through mechanisms involving IL-27 and TLR signaling. Our findings suggest MDSC as novel mediators of tuberculosis in HIV-Mtb co-infected individuals with virologic suppression.

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Therapies for tuberculosis and AIDS: myeloid-derived suppressor cells in focus

Cited by 31 publications

References 158 publications

Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity

Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity

Neutrophils Encompass a Regulatory Subset Suppressing T Cells in Apparently Healthy Cattle and Mice

Monocytic-Myeloid Derived Suppressor Cells of HIV-Infected Individuals With Viral Suppression Exhibit Suppressed Innate Immunity to Mycobacterium tuberculosis

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