title: Cord-blood-derived mesenchymal stromal cells downmodulate CD4+ T-cell activation by inducing IL-10-producing Th1 cells.
abstract: The mechanisms by which mesenchymal stromal cells (MSCs) induce immunomodulation are still poorly understood. In the current work, we show by a combination of polymerase chain reaction (PCR) array, flow cytometry, and multiplex cytokine data analysis that during the inhibition of an alloantigen-driven CD4+ T-cell response, MSCs induce a fraction of CD4+ T-cells to coexpress interferon-γ (IFNγ) and interleukin-10 (IL-10). This CD4+ IFNγ+ IL-10+ cell population shares properties with recently described T-cells originating from switched Th1 cells that start producing IL-10 and acquire a regulatory function. Here we report that IL-10-producing Th1 cells accumulated with time during T-cell stimulation in the presence of MSCs. Moreover, MSCs caused stimulated T-cells to downregulate the IFNγ receptor (IFNγR) without affecting IL-10 receptor expression. Further, the inhibitory effect of MSCs could be reversed by an anti-IFNγR-blocking antibody, indicating that IFNγ is one of the major players in MSC-induced T-cell suppression. Stimulated (and, to a lesser extent, resting) CD4+ T-cells treated with MSCs were able to inhibit the proliferation of autologous CD4+ T-cells, demonstrating their acquired regulatory properties. Altogether, our results suggest that the generation of IL-10-producing Th1 cells is one of the mechanisms by which MSCs can downmodulate an immune response.
authors.affiliation: CHU Sainte-Justine Research Center, Montréal, Quebec, Canada.
authors.forename: Silvia
authors.initials: S
authors.lastname: Selleri
authors.forename: Mame Massar
authors.initials: MM
authors.lastname: Dieng
authors.forename: Simon
authors.initials: S
authors.lastname: Nicoletti
authors.forename: Isabelle
authors.initials: I
authors.lastname: Louis
authors.forename: Christian
authors.initials: C
authors.lastname: Beausejour
authors.forename: Françoise
authors.initials: F
authors.lastname: Le Deist
authors.forename: Elie
authors.initials: E
authors.lastname: Haddad
mesh_terms: D019138:Antibodies, Blocking / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000378:metabolism; D015536:Down-Regulation; D005312:Fetal Blood / Q000166:cytology; D006801:Humans; D056747:Immunomodulation / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis*; D016753:Interleukin-10 / Q000096:biosynthesis*; D008213:Lymphocyte Activation; D059630:Mesenchymal Stem Cells / Q000276:immunology*; D017471:Receptors, Interferon / Q000096:biosynthesis / Q000276:immunology; D053701:Receptors, Interleukin-10 / Q000096:biosynthesis; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism*; D000096743:Interferon gamma Receptor
chemical_list: D019138:Antibodies, Blocking; D007371:Interferon-gamma; D016753:Interleukin-10; D017471:Receptors, Interferon; D053701:Receptors, Interleukin-10; D000096743:Interferon gamma Receptor