IFN-γ production by allogeneic Foxp3+ regulatory T cells is essential for preventing experimental graft-versus-host disease.
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IFN-γ production by allogeneic Foxp3+ regulatory T cells is essential for preventing experimental graft-versus-host disease. / Koenecke, Christian; Lee, Chun-Wei; Thamm, Kristina; Föhse, Lisa; Schafferus, Matthias; Mittrücker, Hans Willi; Floess, Stefan; Huehn, Jochen; Ganser, Arnold; Förster, Reinhold; Prinz, Immo.
in: J IMMUNOL, Jahrgang 189, Nr. 6, 6, 2012, S. 2890-2896.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - IFN-γ production by allogeneic Foxp3+ regulatory T cells is essential for preventing experimental graft-versus-host disease.
AU - Koenecke, Christian
AU - Lee, Chun-Wei
AU - Thamm, Kristina
AU - Föhse, Lisa
AU - Schafferus, Matthias
AU - Mittrücker, Hans Willi
AU - Floess, Stefan
AU - Huehn, Jochen
AU - Ganser, Arnold
AU - Förster, Reinhold
AU - Prinz, Immo
PY - 2012
Y1 - 2012
N2 - It is emerging that CD4+Foxp3+ regulatory T (Treg) cells can produce the proinflammatory cytokine IFN-? when stimulated in a Th1 cytokine environment. In this study, we report that Foxp3+ Treg cells readily produced IFN-? 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-? 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-? after transplantation, suggesting that this cytokine production was alloantigen specific. These IFN-? 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-? production was supporting or rather impairing the immunosuppressive function of Treg cells during GVHD. Blocking of IFN-? 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-?-deficient donor mice, prevented GVHD. This indicated that Treg cell-intrinsic IFN-? production was required for their protective function. In conclusion, our data show that IFN-? produced by Foxp3+ Treg cells has essential immune-regulatory functions that are required for prevention of experimental GVHD.
AB - It is emerging that CD4+Foxp3+ regulatory T (Treg) cells can produce the proinflammatory cytokine IFN-? when stimulated in a Th1 cytokine environment. In this study, we report that Foxp3+ Treg cells readily produced IFN-? 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-? 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-? after transplantation, suggesting that this cytokine production was alloantigen specific. These IFN-? 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-? production was supporting or rather impairing the immunosuppressive function of Treg cells during GVHD. Blocking of IFN-? 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-?-deficient donor mice, prevented GVHD. This indicated that Treg cell-intrinsic IFN-? production was required for their protective function. In conclusion, our data show that IFN-? produced by Foxp3+ Treg cells has essential immune-regulatory functions that are required for prevention of experimental GVHD.
KW - Animals
KW - Cells, Cultured
KW - Disease Models, Animal
KW - Mice
KW - Mice, Inbred BALB C
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - CD4-Positive T-Lymphocytes/immunology/transplantation
KW - CD8-Positive T-Lymphocytes/immunology/transplantation
KW - Forkhead Transcription Factors/biosynthesis
KW - Graft vs Host Disease/genetics/immunology/prevention & control
KW - Immunity, Cellular/genetics
KW - Interferon-gamma/biosynthesis/deficiency/secretion
KW - Isoantigens/biosynthesis/genetics
KW - T-Lymphocytes, Regulatory/immunology/metabolism/secretion
KW - Th1 Cells/immunology/pathology/secretion
KW - Animals
KW - Cells, Cultured
KW - Disease Models, Animal
KW - Mice
KW - Mice, Inbred BALB C
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - CD4-Positive T-Lymphocytes/immunology/transplantation
KW - CD8-Positive T-Lymphocytes/immunology/transplantation
KW - Forkhead Transcription Factors/biosynthesis
KW - Graft vs Host Disease/genetics/immunology/prevention & control
KW - Immunity, Cellular/genetics
KW - Interferon-gamma/biosynthesis/deficiency/secretion
KW - Isoantigens/biosynthesis/genetics
KW - T-Lymphocytes, Regulatory/immunology/metabolism/secretion
KW - Th1 Cells/immunology/pathology/secretion
M3 - SCORING: Journal article
VL - 189
SP - 2890
EP - 2896
JO - J IMMUNOL
JF - J IMMUNOL
SN - 0022-1767
IS - 6
M1 - 6
ER -
