title: Human mesenchymal stromal cells modulate T-cell responses through TNF-α-mediated activation of NF-κB.
abstract: Although mesenchymal stromal cells (MSCs) possess the capacity to modulate immune responses, little is known about the mechanisms that underpin these processes. In this study, we show that immunosupression is mediated by activation of nuclear factor kappa B (NF-κB) in human MSCs. This pathway is activated by TNF-α that is generated following TCR stimulation of T cells. Inhibition of NF-κB through silencing of IκB kinase β or the TNF-α receptor abolishes the immunosuppressive capacity of MSCs. Our data also indicate that MSC-associated NF-κB activation primarily leads to inhibition of T-cell proliferation with little effect on expression of the activation markers CD69 and CD25. Thus, our data support the hypothesis that the TNF-α/NF-κB signalling pathway is required for the initial priming of immunosuppressive function in human MSCs. Interestingly, drugs that interfere with NF-κB activation significantly antagonise the immunoregulatory effect of MSCs, which could have important implications for immunosuppression regimens in the clinic.
authors.affiliation: Mesenchymal and Hematopoietic Stem Cell Laboratory, Foundation for Stem Cell Research, Fundación Inbiomed, San Sebastián, Spain.
authors.forename: Akaitz
authors.initials: A
authors.lastname: Dorronsoro
authors.forename: Izaskun
authors.initials: I
authors.lastname: Ferrin
authors.forename: Juan Manuel
authors.initials: JM
authors.lastname: Salcedo
authors.forename: Emma
authors.initials: E
authors.lastname: Jakobsson
authors.forename: Jon
authors.initials: J
authors.lastname: Fernández-Rueda
authors.forename: Valérie
authors.initials: V
authors.lastname: Lang
authors.forename: Pilar
authors.initials: P
authors.lastname: Sepulveda
authors.forename: Karoline
authors.initials: K
authors.lastname: Fechter
authors.forename: Dan
authors.initials: D
authors.lastname: Pennington
authors.forename: César
authors.initials: C
authors.lastname: Trigueros
mesh_terms: D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D006801:Humans; D051550:I-kappa B Kinase / Q000276:immunology / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism; D037181:Lectins, C-Type / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D059630:Mesenchymal Stem Cells / Q000276:immunology* / Q000378:metabolism*; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism*; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D051550:I-kappa B Kinase; D053645:Interleukin-2 Receptor alpha Subunit; D037181:Lectins, C-Type; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000099192:CD69 Antigens; C508017:IL2RA protein, human
keywords: Immunoregulation; MSC; NF-κB; TNF-α