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    Institut für Virologie und Immunbiologie

    Myeloid-derived suppressor cells (MDSCs)


    MDSCs formely also called myeloid suppressor cells (MSCs) were renamed in 2006 due to confusion with mesenchymal stem cells (also MSCs)(1).

    MDSCs were originally identified in tumor bearing mice (2) and scarcely in chronic inflammatory or infectious diseases (3). Most descriptions of MDSC refer to them by expression of the markers Gr-1 and CD11b and the statement that they represent "a hetergeneous population of immature myeloid cells" (4, 5). Since the Gr-1 and CD11b markers are also expressed by non-suppressive eosinophils and differentiated neutrophils (6) more refined analyses are requred to define MDSCs.  

    In mice and later in humans two subsets have been described from tumor-bearing mice (7, 8) but the same cells we could sort from spleens of healthy mice based on quantitative differences in Gr-1 and CD11b marker expression (6) or by the criteria shown in the figure below that include morphology (H&E staining), surface markers and - most importantly - suppressive capacity!

     

     

    Our MDSC research

    Our group was the first that described a protocol for the in vitro generation of murine MDSC from bone marrow precursor cells using GM-CSF in a three day culture protocol (9).

    We also found that the in vivo use of Gr-1 (Rb6-8C5 clone) recognizing epitopes on the Ly-6C and Ly-6G molecules is limited for depletion experiments only under inflammatory conditions but not in healthy mice (10). The Gr-1 antibody remained for at least 4 days on the cell surface. Monocytic cells showed STAT1, STAT3 and STAT5 phosphorylation after Ly-6C ligation and were induced to differentiate transiently into macrophages. Induction of apoptosis by Gr-1 through Ly-6G of pre-neutrophils was prevented, most likely by their expression of the Bcl-2 family member Mcl-1. MDSC suppressor activity was only transiently interrupted for both subsets (10).

     

     

    The method to generate MDSC from non-suppressive precursor cells in vitro enabled us to investigate the activation requirements of MDSC. We found that only combined signals through IFN-g and LPS led to suppressor activity, while both factors alone were unable to do so (6).

     

     

    Current projects

    Together with the Walzl-group we found that Mycobacterium tuberculosis (Mtb) patients show increased frequencies of MDSC in their blood (11). More recent data of our lab indicate that Mtb targets MDSC to evade phagolysosomal degradation and activate immunosuppressive activity. The role of new entry receptors and specific endosomal compartments in this immune evasion process are investigated.

    Other studies include the analysis of the signaling pathways of GM-CSF mediated "licensing" of monocytic cells into MDSC.

    We also follow the homing patterns of MDSC in mice and its relation to T cell suppressor function.

     

    References

     

    1.         Gabrilovich, D. I., V. Bronte, S. H. Chen, M. P. Colombo, A. Ochoa, S. Ostrand-Rosenberg, and H. Schreiber. 2007. The terminology issue for myeloid-derived suppressor cells. Cancer Res 67: 425; author reply 426.

    2.         Bronte, V., M. Wang, W. W. Overwijk, D. R. Surman, F. Pericle, S. A. Rosenberg, and N. P. Restifo. 1998. Apoptotic death of CD8+ T lymphocytes after immunization: induction of a suppressive population of Mac-1+/Gr-1+ cells. J. Immunol. 161: 5313-5320.

    3.         Serafini, P., C. De Santo, I. Marigo, S. Cingarlini, L. Dolcetti, G. Gallina, P. Zanovello, and V. Bronte. 2004. Derangement of immune responses by myeloid suppressor cells. Cancer Immunol Immunother: 64-72.

    4.         Gabrilovich, D. I., and S. Nagaraj. 2009. Myeloid-derived suppressor cells as regulators of the immune system. Nature reviews 9: 162-174.

    5.         Gabrilovich, D. I., S. Ostrand-Rosenberg, and V. Bronte. 2012. Coordinated regulation of myeloid cells by tumours. Nature reviews 12: 253-268.

    6.         Greifenberg, V., E. Ribechini, S. Rossner, and M. B. Lutz. 2009. Myeloid-derived suppressor cell activation by combined LPS and IFN-gamma treatment impairs DC development. Eur. J. Immunol. 39: 2865-2876.

    7.         Youn, J. I., S. Nagaraj, M. Collazo, and D. I. Gabrilovich. 2008. Subsets of myeloid-derived suppressor cells in tumor-bearing mice. J Immunol 181: 5791-5802.

    8.         Movahedi, K., M. Guilliams, J. Van den Bossche, R. Van den Bergh, C. Gysemans, A. Beschin, P. De Baetselier, and J. A. Van Ginderachter. 2008. Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity. Blood 111: 4233-4244.

    9.         Rößner, S., C. Voigtländer, C. Wiethe, J. Hänig, C. Seifarth, and M. B. Lutz. 2005. Myeloid dendritic cell precursors generated from bone marrow suppress T cell responses via cell contact and nitric oxide production in vitro. Eur. J. Immunol. 35: 3533-3544.

    10.      Ribechini, E., P. J. Leenen, and M. B. Lutz. 2009. Gr-1 antibody induces STAT signaling, macrophage marker expression and abrogation of myeloid-derived suppressor cell activity in BM cells. Eur. J. Immunol. 39: 3538-3551.

    11.      du Plessis, N., L. Loebenberg, M. Kriel, F. von Groote-Bidlingmaier, E. Ribechini, A. G. Loxton, P. D. van Helden, M. B. Lutz, and G. Walzl. 2013. Increased Frequency of Myeloid Derived Suppressor Cells during Active Tuberculosis and Following Recent Mycobacterium tuberculosis Infection Suppresses T Cell Function. Am J Respir Crit Care Med.

     

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