title: Human CD4+ HLA-G+ regulatory T cells are potent suppressors of graft-versus-host disease in vivo.
abstract: CD4(+) T cells expressing the immunotolerizing molecule HLA-G have been described as a unique human thymus-derived regulatory T (tTreg) cell subset involved in immunoregulation and parenchymal homeostasis during infectious and autoimmune inflammation. We compared properties and molecular characteristics of human CD4(+)HLA-G(+) with those of CD4(+)CD25(+)FoxP3-expressing tTreg cells using in vitro studies of T-cell receptor (TCR) signaling, single-cell electrophysiology, and functional in vivo studies. Both tTreg populations are characterized by alterations in proximal-signaling pathways on TCR stimulation and a hyperpolarization of the plasma membrane when compared to conventional CD4(+) T cells. However, both clearly differ in phenotype and pattern of secreted cytokines, which results in distinct mechanisms of suppression: While CD4(+)HLA-G(+) cells secrete high levels of inhibitory molecules (IL-10, soluble HLA-G, IL-35), CD4(+)CD25(+)FoxP3(+) cells express these molecules at significantly lower levels and seem to exert their function mainly in a contact-dependent manner via cyclic adenosine-monophosphate. Finally we demonstrate that human CD4(+)HLA-G(+) tTreg cells significantly ameliorated graft-versus-host disease in a humanized mouse model as a first proof of their in vivo relevance. Our data further characterize and establish CD4(+)HLA-G(+) cells as a potent human tTreg population that can modulate polyclonal adaptive immune responses in vivo and thus being a promising candidate for potential clinical applications in the future.
authors.affiliation: Department of Neurology and.
authors.forename: Susann
authors.initials: S
authors.lastname: Pankratz
authors.affiliation: Department of Neurology and.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bittner
authors.affiliation: Department of Neurology and.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Herrmann
authors.affiliation: Department of Neurology, University of Würzburg, Würzburg, Germany.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Schuhmann
authors.affiliation: Department of Neurology and.
authors.forename: Tobias
authors.initials: T
authors.lastname: Ruck
authors.affiliation: Department of Neurology and Institute of Physiology I, Department of Neuropathophysiology, University of Münster, Münster, Germany; and.
authors.forename: Sven G
authors.initials: SG
authors.lastname: Meuth
authors.affiliation: Department of Neurology and heinz.wiendl@ukmuenster.de.
authors.forename: Heinz
authors.initials: H
authors.lastname: Wiendl
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D020013:Calcium Signaling; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000032:analysis; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D059951:HLA-G Antigens / Q000276:immunology; D064593:Heterografts; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods*; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D007963:Leukocytes, Mononuclear / Q000637:transplantation*; D008213:Lymphocyte Activation; D008564:Membrane Potentials; D051379:Mice; D016688:Mice, Inbred NOD; D013047:Specific Pathogen-Free Organisms; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000637:transplantation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000637:transplantation
chemical_list: D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D059951:HLA-G Antigens; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit
keywords: human leukocyte antigen G; humanized mouse model; immune tolerance; membrane potential of tTreg cells