1. IFN-&ggr; Production by Allogeneic Foxp3+ Regulatory T Cells Is Essential for Preventing Experimental Graft-versus-Host Disease.
- Author
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Koenecke, Christian, Chun-Wei Lee, Thamm, Kristina, Föhse, Lisa, Schafferus, Matthias, Mittrücker, Hans-Willi, Floess, Stefan, Jochen Huehn, Ganser, Arnold, Förster, Reinhold, and Prinz, Immo
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INTERFERONS , *CD4 antigen , *FORKHEAD transcription factors , *T cells , *GRAFT versus host disease , *CYTOKINES , *IMMUNOSUPPRESSION , *LOCUS (Genetics) - Abstract
It is emerging that CD4+Foxp3+ regulatory T (Treg) cells can produce the proinflammatory cytokine IFN-&ggr; when stimulated in a Thl cytokine environment. In this study, we report that Foxp3+ Treg cells readily produced IFN-&ggr; in vivo in a highly inflammatory model of graft-versus-host disease (GVHD) and during a Thl-dominated immune response to intracellular bacteria. Moreover, stimulation in vitro via TCR in the presence of IL-12 alone was sufficient to induce IFN-&ggr; 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-&ggr; after transplantation, suggesting that this cytokine production was alloantigen specific. These IFN-&ggr; 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-&ggr; production was supporting or rather impairing the immunosuppressive function of Treg cells during GVHD. Blocking of IFN-&ggr; 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-&ggr;-deficient donor mice, prevented GVHD. This indicated that Treg cell-intrinsic IFN-&ggr; production was required for their protective function. In conclusion, our data show that IFN-&ggr; produced by Foxp3+ Treg cells has essential immune-regulatory functions that are required for prevention of expérimentai GVHD. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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