title: IFN-γ production by allogeneic Foxp3+ regulatory T cells is essential for preventing experimental graft-versus-host disease.
abstract: It is emerging that CD4+Foxp3+ regulatory T (Treg) cells can produce the proinflammatory cytokine IFN-γ when stimulated in a Th1 cytokine environment. In this study, we report that Foxp3+ Treg cells readily produced IFN-γ in vivo in a highly inflammatory model of graft-versus-host disease (GVHD) and during a Th1-dominated immune response to intracellular bacteria. Moreover, stimulation in vitro via TCR in the presence of IL-12 alone was sufficient to induce IFN-γ production by Treg cells in a dose-dependent manner. Transfer of donor Treg cells can prevent lethal GVHD; therefore, we used this model as a robust readout for in vivo Treg function. Interestingly, >50% of allogeneic donor, but not residual recipient Foxp3+ Treg cells produced IFN-γ after transplantation, suggesting that this cytokine production was alloantigen specific. These IFN-γ producers were stable Foxp3+ Treg cells because methylation analysis of the Foxp3 gene locus of transferred and reisolated Treg cells during GVHD showed a fully demethylated Treg-specific-demethylated region. Next, we addressed whether IFN-γ production was supporting or rather impairing the immunosuppressive function of Treg cells during GVHD. Blocking of IFN-γ with specific mAb completely abolished the beneficial effect of donor Treg cells. We could further show that only wild-type Treg cells, but not Treg cells from IFN-γ-deficient donor mice, prevented GVHD. This indicated that Treg cell-intrinsic IFN-γ production was required for their protective function. In conclusion, our data show that IFN-γ produced by Foxp3+ Treg cells has essential immune-regulatory functions that are required for prevention of experimental GVHD.
authors.affiliation: Institute of Immunology, Hannover Medical School, 30625 Hannover, Germany. christian@mh-hannover.de
authors.forename: Christian
authors.initials: C
authors.lastname: Koenecke
authors.forename: Chun-Wei
authors.initials: CW
authors.lastname: Lee
authors.forename: Kristina
authors.initials: K
authors.lastname: Thamm
authors.forename: Lisa
authors.initials: L
authors.lastname: Föhse
authors.forename: Matthias
authors.initials: M
authors.lastname: Schafferus
authors.forename: Hans-Willi
authors.initials: HW
authors.lastname: Mittrücker
authors.forename: Stefan
authors.initials: S
authors.lastname: Floess
authors.forename: Jochen
authors.initials: J
authors.lastname: Huehn
authors.forename: Arnold
authors.initials: A
authors.lastname: Ganser
authors.forename: Reinhold
authors.initials: R
authors.lastname: Förster
authors.forename: Immo
authors.initials: I
authors.lastname: Prinz
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000096:biosynthesis*; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control*; D007111:Immunity, Cellular / Q000235:genetics; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000172:deficiency / Q000378:metabolism; D007519:Isoantigens / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007519:Isoantigens; D007371:Interferon-gamma