TY - JOUR
T1 - Hierarchy of immunosuppressive strength among myeloid-derived suppressor cell subsets is determined by GM-CSF
AU - Dolcetti, Luigi
AU - Peranzoni, Elisa
AU - Ugel, Stefano
AU - Marigo, Ilaria
AU - Gomez, Audry Fernandez
AU - Mesa, Circe
AU - Geilich, Markus
AU - Winkels, Gregor
AU - Traggiai, Elisabetta
AU - Casati, Anna
AU - Grassi, Fabio
AU - Bronte, Vincenzo
PY - 2010/1
Y1 - 2010/1
N2 - CD11b+/Gr-1+ myeloid-derived suppressor cells (MDSC) contribute to tumor immune evasion by restraining the activity of CD8 + T-cells. Two major MDSC subsets were recently shown to play an equal role in MDSC-induced immune dysfunctions: monocytic- and granulocytic-like. We isolated three fractions of MDSC, i.e. CD11b +/Gr-1high, CD11b+/ Gr-1int, and CD11b+/Gr-1low populations that were characterized morphologically, phenotypically and functionally in different tumor models. In vitro assays showed that CD11b+/Gr-1int cell subset, mainly comprising monocytes and myeloid precursors, was always capable to suppress CD8+ T-cell activation, while CD11b+/Gr-1 high cells, mostly granulocytes, exerted appreciable suppression only in some tumor models and when present in high numbers. The CD11b +/Gr-1int but not CD11b+/Gr-1high cells were also immunosuppressive in vivo following adoptive transfer. CD11b+/Gr-1low cells retained the immunosuppressive potential in most tumor models. Gene silencing experiments indicated that GM-CSF was necessary to induce preferential expansion of both CD11b +/Gr-1int and CD11b+/Gr-1low subsets in the spleen of tumor-bearing mice and mediate tumor-induced tolerance whereas G-CSF, which preferentially expanded CD11b+/Gr-1high cells, did not create such immunosuppressive environment. GM-CSF also acted on granulocyte-macrophage progenitors in the bone marrow inducing local expansion of CD11b+/Gr-1low cells. These data unveil a hierarchy of immunoregulatory activity among MDSC subsets that is controlled by tumor-released GM-CSF.
AB - CD11b+/Gr-1+ myeloid-derived suppressor cells (MDSC) contribute to tumor immune evasion by restraining the activity of CD8 + T-cells. Two major MDSC subsets were recently shown to play an equal role in MDSC-induced immune dysfunctions: monocytic- and granulocytic-like. We isolated three fractions of MDSC, i.e. CD11b +/Gr-1high, CD11b+/ Gr-1int, and CD11b+/Gr-1low populations that were characterized morphologically, phenotypically and functionally in different tumor models. In vitro assays showed that CD11b+/Gr-1int cell subset, mainly comprising monocytes and myeloid precursors, was always capable to suppress CD8+ T-cell activation, while CD11b+/Gr-1 high cells, mostly granulocytes, exerted appreciable suppression only in some tumor models and when present in high numbers. The CD11b +/Gr-1int but not CD11b+/Gr-1high cells were also immunosuppressive in vivo following adoptive transfer. CD11b+/Gr-1low cells retained the immunosuppressive potential in most tumor models. Gene silencing experiments indicated that GM-CSF was necessary to induce preferential expansion of both CD11b +/Gr-1int and CD11b+/Gr-1low subsets in the spleen of tumor-bearing mice and mediate tumor-induced tolerance whereas G-CSF, which preferentially expanded CD11b+/Gr-1high cells, did not create such immunosuppressive environment. GM-CSF also acted on granulocyte-macrophage progenitors in the bone marrow inducing local expansion of CD11b+/Gr-1low cells. These data unveil a hierarchy of immunoregulatory activity among MDSC subsets that is controlled by tumor-released GM-CSF.
KW - GM-CSF
KW - Immunosuppression
KW - Myeloid-derived suppressor cells subsets
KW - Tolerance
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U2 - 10.1002/eji.200939903
DO - 10.1002/eji.200939903
M3 - Article
C2 - 19941314
AN - SCOPUS:74249101123
VL - 40
SP - 22
EP - 35
JO - European Journal of Immunology
JF - European Journal of Immunology
SN - 0014-2980
IS - 1
ER -