IFNγR signaling mediates alloreactive T-cell trafficking and GVHD

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 (IFN gamma R-/-) 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 IFN gamma R-/- Tconv to GVHD target organs, especially the gastrointestinal (GI) tract. We show that the chemokine receptor CXCR3 is induced via IFN gamma R-mediated signaling and partially contributes to the trafficking of WT Tconv to GVHD target organs. Indeed, CXCR3(-/-) Tconv recapitulate the reduced GVHD potential of IFN gamma R-/- Tconv in a minor-mismatched GVHD model. Most importantly, IFN gamma R-/- (and CXCR3(-/-)) Tconv mediate a robust and beneficial GvL effect. In addition, we show that IFN gamma R-/- 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 pro-duce interferon gamma(IFN gamma), suggesting that the IFN gamma R signaling pathway is the major mechanism for both Tregs and Tconv to migrate to GVHD target organs. Finally, pharmacologic inhibition of IFN gamma R signaling with inhibitors of JAK1/JAK2, which are mediators of IFN gamma R 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. (Blood. 2012; 120(19):4093-4103)