Authors:
Jaebok Choi, Edward D. Ziga, Julie Ritchey, Lynne Collins, Julie L. Prior, Matthew L. Cooper, David Piwnica-Worms, and John F. DiPersio
Summary:
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 (IFNγR-/-) allogeneic Tconv, which possess normal allo-reactivity and cytotoxicity, induce significantly less GvHD than wild-type (WT) Tconv. This effect is mediated by altered trafficking of IFNγR-/- Tconv to GvHD target organs, especially gastrointestinal (GI) tract. We show that the chemokine receptor CXCR3 is induced via IFNγR-mediated signaling and partially contributes to the trafficking of WT Tconv to GvHD target organs. Indeed, CXCR3-/- Tconv recapitulate the reduced GvHD potential of IFNγR-/- Tconv in a minor-mismatched GvHD model. Most importantly, IFNγR-/- (and CXCR3-/-) Tconv mediate a robust and beneficial GvL effect. In addition, we show that IFNγR-/- regulatory T cells (Tregs) are fully suppressive in vitro while defective in suppressor function in vivo and that WT Tregs suppress GvHD in vivo only when allogeneic Tconv produce interferon gamma (IFNγ), suggesting that the IFNγR signaling pathway is the major mechanism for both Tregs and Tconv to migrate to GvHD target organs. Finally, pharmacologic inhibition of IFNγR signaling with inhibitors of JAK1/JAK2, which are mediators of IFNγR 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.
Source:
Blood; (09/12/12)