title: Tumor-induced myeloid-derived suppressor cell subsets exert either inhibitory or stimulatory effects on distinct CD8+ T-cell activation events.
abstract: Tumor growth coincides with an accumulation of myeloid-derived suppressor cells (MDSCs), which exert immune suppression and which consist of two main subpopulations, known as monocytic (MO) CD11b(+) CD115(+) Ly6G(-) Ly6C(high) MDSCs and granulocytic CD11b(+) CD115(-) Ly6G(+) Ly6C(int) polymorphonuclear (PMN)-MDSCs. However, whether these distinct MDSC subsets hamper all aspects of early CD8(+) T-cell activation--including cytokine production, surface marker expression, survival, and cytotoxicity--is currently unclear. Here, employing an in vitro coculture system, we demonstrate that splenic MDSC subsets suppress antigen-driven CD8(+) T-cell proliferation, but differ in their dependency on IFN-γ, STAT-1, IRF-1, and NO to do so. Moreover, MO-MDSC and PMN-MDSCs diminish IL-2 levels, but only MO-MDSCs affect IL-2Rα (CD25) expression and STAT-5 signaling. Unexpectedly, however, both MDSC populations stimulate IFN-γ production by CD8(+) T cells on a per cell basis, illustrating that some T-cell activation characteristics are actually stimulated by MDSCs. Conversely, MO-MDSCs counteract the activation-induced change in CD44, CD62L, CD162, and granzyme B expression, while promoting CD69 and Fas upregulation. Together, these effects result in an altered CD8(+) T-cell adhesiveness to the extracellular matrix and selectins, sensitivity to FasL-mediated apoptosis, and cytotoxicity. Hence, MDSCs intricately influence different CD8(+) T-cell activation events in vitro, whereby some parameters are suppressed while others are stimulated.
authors.affiliation: Myeloid Cell Immunology Laboratory, VIB, Brussels, Belgium; Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Elio
authors.initials: E
authors.lastname: Schouppe
authors.forename: Camille
authors.initials: C
authors.lastname: Mommer
authors.forename: Kiavash
authors.initials: K
authors.lastname: Movahedi
authors.forename: Damya
authors.initials: D
authors.lastname: Laoui
authors.forename: Yannick
authors.initials: Y
authors.lastname: Morias
authors.forename: Conny
authors.initials: C
authors.lastname: Gysemans
authors.forename: Ariane
authors.initials: A
authors.lastname: Luyckx
authors.forename: Patrick
authors.initials: P
authors.lastname: De Baetselier
authors.forename: Jo A
authors.initials: JA
authors.lastname: Van Ginderachter
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D000950:Antigens, Ly / Q000378:metabolism; D017209:Apoptosis / Q000276:immunology; D039481:CD11b Antigen / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002448:Cell Adhesion / Q000276:immunology; D002460:Cell Line; D049109:Cell Proliferation; D005260:Female; D053804:Granzymes / Q000096:biosynthesis; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D019041:L-Selectin / Q000096:biosynthesis; D037181:Lectins, C-Type / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology; D009569:Nitric Oxide / Q000378:metabolism; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D015854:Up-Regulation; D019014:fas Receptor / Q000096:biosynthesis; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000950:Antigens, Ly; D039481:CD11b Antigen; D053804:Granzymes; D018960:Hyaluronan Receptors; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D019041:L-Selectin; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D009569:Nitric Oxide; D016186:Receptor, Macrophage Colony-Stimulating Factor; D050794:STAT1 Transcription Factor; D050799:STAT5 Transcription Factor; D019014:fas Receptor; D000099192:CD69 Antigens; C491899:Fas protein, mouse; C508018:Il2ra protein, mouse; C494192:Ly-6C antigen, mouse; C480309:Ly6G antigen, mouse; C084882:P-selectin ligand protein; C494080:Stat1 protein, mouse; C509214:Gzmb protein, mouse
keywords: CD8+ T-cell activation; CD8+ T-cell suppression; Monocytic myeloid-derived suppressor cell (MO-MDSC); Nitric oxide; Polymorphonuclear MDSC (PMN-MDSC)