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| MDSCs: Gabrilovich & Nagaraj, Nat Rev Immunol 2009 |
Recently, researchers have found a new subset of immune cells that functions to suppress immunity in multiple diseases. Early research has identified them as myeloid-derived suppressor
cells (MDSCs), a heterogenous group of immature myeloid cells, divided into granulocytic or monocytic subsets (CD15 or CD14). Recent research has focused on their role in tumor immunology; Hosoi et al showed that during adoptive CTL (cytotoxic T lymphocyte) treatment of cancer (melanoma), CTLs triggered expansion of MDSCs that eventually outnumbered CTLs, secreted reactive oxygen and nitrogen species, and prevented further proliferation of CTLs. This research in cancer biology shows that immunotherapy and immune response can trigger a counter-regulatory response that dampens the immune system. In a recent paper, Ankita Garg and Stephen Spector tested the roles of MDSCs in viral infection, specifically HIV/AIDS, and found a very similar suppressive effect. As not much is known about the mechanisms behind how MDSCs function in the immune response, these authors used HIV infection of PBMCs and co-culture techniques to explore how MDSCs suppress immunity, covering their expansion, function, and mechanisms of function.
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| Origin of MDSCs; Gabrilovich & Nagaraj, Nat Rev Immunol 2009 |
To start, the authors treated PBMCs (peripheral blood mononuclear cells) with heat-inactivated or infectious HIV, or gp120, a HIV envelope glycoprotein responsible for binding to the CD4 co-receptor on a helper T cell and allowing the HIV envelope glycoprotein gp41 to contact the host cell membrane and promote viral fusion (see
HIV and Neurocognitive Dysfunction). Both infectious HIV and inactivated HIV/gp120 were able to induce expansion of MDSCs (in this paper gated as
CD11b+CD33+CD14+HLA-DR-/lo; see note), suggesting that viral replication is not necessary of induction of MDSCs. Next, they looked that how gp120 was able to induced MDSC expansion, and found that PBMCs cultured with gp120 conditioned media showed increased an MDSC population, and found increased levels of IL-6, a major inflammatory cytokine, in gp120-treated PBMC supernatants, leading them to hypothesize that IL-6 was responsible for inducing MDSCs. They confirmed this by showing IL-6 neutralization inhibited MDSC expansion. Furthermore, they surmised that IL-6 would be acting through its STAT3 pathway (a major pathway for IL-6 signaling), and found increased levels of phosphorylated STAT3 (pSTAT3) in gp120-treated PBMCs. They showed that IL-6 neutralization completely abolished pSTAT3 expression in gp120-treated PBMCs, showing that IL-6 may cause MDSC expansion via signaling through the STAT3 pathway.
