| First Author | Koenecke C | Year | 2012 |
| Journal | J Immunol | Volume | 189 |
| Issue | 6 | Pages | 2890-6 |
| PubMed ID | 22869903 | Mgi Jnum | J:189843 |
| Mgi Id | MGI:5447117 | Doi | 10.4049/jimmunol.1200413 |
| Citation | Koenecke C, et al. (2012) IFN-gamma production by allogeneic Foxp3+ regulatory T cells is essential for preventing experimental graft-versus-host disease. J Immunol 189(6):2890-6 |
| abstractText | It is emerging that CD4+Foxp3+ regulatory T (Treg) cells can produce the proinflammatory cytokine IFN-gamma when stimulated in a Th1 cytokine environment. In this study, we report that Foxp3+ Treg cells readily produced IFN-gamma 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-gamma 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-gamma after transplantation, suggesting that this cytokine production was alloantigen specific. These IFN-gamma 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-gamma production was supporting or rather impairing the immunosuppressive function of Treg cells during GVHD. Blocking of IFN-gamma 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-gamma-deficient donor mice, prevented GVHD. This indicated that Treg cell-intrinsic IFN-gamma production was required for their protective function. In conclusion, our data show that IFN-gamma produced by Foxp3+ Treg cells has essential immune-regulatory functions that are required for prevention of experimental GVHD. |
