title: IDO-independent suppression of T cell effector function by IFN-γ-licensed human mesenchymal stromal cells.
abstract: Human bone marrow-derived mesenchymal stromal cells (MSCs) inhibit proliferation of activated T cells, and IFN-γ plays an important role in this process. This IFN-γ-licensed veto property is IDO-dependent. To further decipher the mechanistic underpinnings of MSC veto function on T cells, we investigated the effect of MSCs and IFN-γ-licensed MSCs on T cell effector function as assayed by cytokine secretion of T cells. Although MSCs and IFN-γ-licensed MSCs inhibit T cell proliferation, only IFN-γ-licensed MSCs significantly inhibit Th1 cytokine (IFN-γ, TNF-α, and IL-2) production by T cells. Additionally, IFN-γ-licensed MSCs inhibit T cell degranulation as well as single, double, and triple cytokine-producing T cells. Although IFN-γ-licensed MSCs upregulate their IDO activity, we found that MSC IDO catalytic function is dispensable with regard to MSC-driven inhibition of T cell effector function. Novel flow cytometry based functional screening of MSC-expressed, IFN-γ-licensed inhibitory molecules identified B7H1 and B7DC/PD1 pathways as essential effectors in blocking T cell function. Small interfering RNA-mediated blocking of B7H1 and B7DC reverses the inhibitory potential of IFN-γ-licensed MSCs on T cell effector function. Mechanistic analysis revealed that clustering of MHC and coinhibitory molecules are indispensable for the inhibitory effect of IFN-γ MSCs. Although exogenous IL-2 reverses B7H1-Ig-mediated inhibition of T cell proliferation, it does not affect the veto function of IFN-γ MSCs on both T cell proliferation and effector function. Our results reveal a new immunosuppressive property of IFN-γ-licensed MSCs that inhibits T cell effector function independent of IDO but through the ligands for PD1.
authors.affiliation: Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322.
authors.forename: Raghavan
authors.initials: R
authors.lastname: Chinnadurai
authors.forename: Ian B
authors.initials: IB
authors.lastname: Copland
authors.forename: Seema R
authors.initials: SR
authors.lastname: Patel
authors.forename: Jacques
authors.initials: J
authors.lastname: Galipeau
mesh_terms: D060890:B7-H1 Antigen / Q000235:genetics / Q000378:metabolism; D001854:Bone Marrow Cells; D015550:Cell Degranulation / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism*; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D059630:Mesenchymal Stem Cells / Q000276:immunology / Q000378:metabolism*; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; C576710:IDO1 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007376:Interleukin-2; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma