|MDSCs: Gabrilovich & Nagaraj, Nat Rev Immunol 2009|
|Origin of MDSCs; Gabrilovich & Nagaraj, Nat Rev Immunol 2009|
After discovering a probable mechanism behind MDSC expansion during infection, the authors then tested the function of MDSCs and the mechanisms behind their (suppressive) function. They found that when they co-cultured MDSCs expanded under gp120 with CD4 or CD8 T cells, they found that MDSCs were able to reduce the production of IFN-gamma, a key pro-inflammatory and anti-viral cytokine. However, when they co-cultured MDSCs with these T cell subsets in different chambers of a transwell, the suppression of IFN-gamma was abrogated, suggesting that MDSCs may require cell-to-cell contact to suppress the activity of T cells during the immune response to infection. Further, they found that gp120-expanded MDSCs expressed high levels of reactive oxygen and nitrogen species (ROS, iNOS, Arg1); these reactive species have been shown by Nagaraj et al to prevent CD8 T cells from interacting with pMHC (antigen-presenting MHC molecule) and responding to specific antigens by altering the CD8-TCR complex. Inhibiting ROS or iNOS while MDSCs were co-cultured with T cells also abrogated suppression of CD8 and CD4 T cell IFN-gamma production.
|Figure 6, D: Expansion of Tregs|
Through multiple stimulation and co-culture experiments, these authors were able to discover aspects pertaining to MDSC proliferation and function. They found that IL-6 induced MDSC expansion via STAT3 signaling, and that this pathway is active during HIV infection. Furthermore, they elucidated the suppressive role of MDSC by showing that these subset of cells can suppress IFN-gamma production by producing reactive nitrogen and oxygen species to hinder the T cell response and also induce T cell IL-10 secretion. Furthermore, they found that MDSCs, in addition to suppressing immunity directly, also suppress immunity indirectly by stimulating Treg proliferation. Lastly, to show that these in vitro studies were relevant to human HIV infection, they sampled the blood of patients with untreated HIV infection and found an increased population of MDSCs (as well as higher plasma IL-6) compared to HIV-uninfected individuals. Thus, these authors not only have elucidated the role of MDSCs in immune suppression and mechanisms behind their action, they discovered a possible mechanism for the the severe immunodeficiency during HIV/AIDS infection. These new findings give scientists yet another target for HIV treatment, though because relatively little is known about this new subset, it may be a while until scientists can confidently manipulate the immune system and restore normal immune function through regulation of MDSCs. While the findings of this article have provided valuable insight into immunosuppression during HIV infection, further studies will need to investigate MDSC biology in more detail and using in vivo methods, to confirm that these MDSC functions are indeed occurring in human disease and infection.
CD11b - integrin alpha M, expressed by monocytes (and granulocytes, macrophages)
CD33 - transmembrane receptor specifically expressed by myeloid lineage cells
CD14 - a PRR (pattern recognitino receptor) expressed by monocytes (and macrophages)
HLA-DR - human MHC class II, pathologically low expression on monocytes
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