| First Author | Choi J | Year | 2012 |
| Journal | Blood | Volume | 120 |
| Issue | 19 | Pages | 4093-103 |
| PubMed ID | 22972985 | Mgi Jnum | J:191286 |
| Mgi Id | MGI:5461409 | Doi | 10.1182/blood-2012-01-403196 |
| Citation | Choi J, et al. (2012) IFNgammaR signaling mediates alloreactive T-cell trafficking and GVHD. Blood 120(19):4093-103 |
| abstractText | The clinical goal of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is to minimize GVHD while maintaining GvL. Here, we show that interferon gamma receptor-deficient (IFNgammaR(-/-)) allogeneic Tconv, which possess normal alloreactivity and cytotoxicity, induce significantly less GVHD than wild-type (WT) Tconv. This effect is mediated by altered trafficking of IFNgammaR(-/-) Tconv to GVHD target organs, especially the gastrointestinal (GI) tract. We show that the chemokine receptor CXCR3 is induced via IFNgammaR-mediated signaling and partially contributes to the trafficking of WT Tconv to GVHD target organs. Indeed, CXCR3(-/-) Tconv recapitulate the reduced GVHD potential of IFNgammaR(-/-) Tconv in a minor-mismatched GVHD model. Most importantly, IFNgammaR(-/-) (and CXCR3(-/-)) Tconv mediate a robust and beneficial GvL effect. In addition, we show that IFNgammaR(-/-) regulatory T cells (Tregs) are fully suppressive in vitro although defective in suppressor function in vivo and that WT Tregs suppress GVHD in vivo only when allogeneic Tconv produce interferon gamma (IFNgamma), suggesting that the IFNgammaR signaling pathway is the major mechanism for both Tregs and Tconv to migrate to GVHD target organs. Finally, pharmacologic inhibition of IFNgammaR signaling with inhibitors of JAK1/JAK2, which are mediators of IFNgammaR signaling, results in the decreased expression of CXCR3 and reduced GVHD and improved survival after allo-HSCT and this effect is mediated by altered trafficking of Tconv to GVHD target organs. |
