title: IFNγ Regulates Activated Vδ2+ T Cells through a Feedback Mechanism Mediated by Mesenchymal Stem Cells.
abstract: γδ T cells play a role in a wide range of diseases such as autoimmunity and cancer. The majority of circulating human γδ T lymphocytes express a Vγ9Vδ2+ (Vδ2+) T cell receptor (TCR) and following activation release pro-inflammatory cytokines. In this study, we show that IFNγ, produced by Vδ2+ cells, activates mesenchymal stem cell (MSC)-mediated immunosupression, which in turn exerts a negative feedback mechanism on γδ T cell function ranging from cytokine production to proliferation. Importantly, this modulatory effect is limited to a short period of time (<24 hours) post-T cell activation, after which MSCs can no longer exert their immunoregulatory capacity. Using genetically modified MSCs with the IFNγ receptor 1 constitutively silenced, we demonstrate that IFNγ is essential to this process. Activated γδ T cells induce expression of several factors by MSCs that participate in the depletion of amino acids. In particular, we show that indolamine 2,3-dioxygenase (IDO), an enzyme involved in L-tryptophan degradation, is responsible for MSC-mediated immunosuppression of Vδ2+ T cells. Thus, our data demonstrate that γδ T cell responses can be immuno-modulated by different signals derived from MSC.
authors.affiliation: Fundación Inbiomed, Foundation for Stem Cell Research, Mesenchymal Stem Cell Laboratory, Paseo Mikeletegi, San Sebastián, Spain.
authors.forename: Karoline
authors.initials: K
authors.lastname: Fechter
authors.affiliation: Fundación Inbiomed, Foundation for Stem Cell Research, Mesenchymal Stem Cell Laboratory, Paseo Mikeletegi, San Sebastián, Spain.
authors.forename: Akaitz
authors.initials: A
authors.lastname: Dorronsoro
authors.affiliation: Fundación Inbiomed, Foundation for Stem Cell Research, Mesenchymal Stem Cell Laboratory, Paseo Mikeletegi, San Sebastián, Spain.
authors.forename: Emma
authors.initials: E
authors.lastname: Jakobsson
authors.affiliation: Fundación Inbiomed, Foundation for Stem Cell Research, Mesenchymal Stem Cell Laboratory, Paseo Mikeletegi, San Sebastián, Spain.
authors.forename: Izaskun
authors.initials: I
authors.lastname: Ferrin
authors.affiliation: Fundación Inbiomed, Foundation for Stem Cell Research, Mesenchymal Stem Cell Laboratory, Paseo Mikeletegi, San Sebastián, Spain.
authors.forename: Valérie
authors.initials: V
authors.lastname: Lang
authors.affiliation: Fundación para la Investigación Hospital Universitario La Fe, Valencia, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Sepulveda
authors.affiliation: Blizard Institute, Barts and The London School of Medicine, Queen Mary University of London, London, United Kingdom.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Pennington
authors.affiliation: Fundación Inbiomed, Foundation for Stem Cell Research, Mesenchymal Stem Cell Laboratory, Paseo Mikeletegi, San Sebastián, Spain.
authors.forename: César
authors.initials: C
authors.lastname: Trigueros
mesh_terms: D001854:Bone Marrow Cells / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D025461:Feedback, Physiological / Q000187:drug effects; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D007371:Interferon-gamma / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000502:physiology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
chemical_list: D016692:Receptors, Antigen, T-Cell, gamma-delta; D007371:Interferon-gamma