TY - JOUR
T1 - IFNγR signaling mediates alloreactive T-cell trafficking and GVHD
AU - Choi, Jaebok
AU - Ziga, Edward D.
AU - Ritchey, Julie
AU - Collins, Lynne
AU - Prior, Julie L.
AU - Cooper, Matthew L.
AU - Piwnica-Worms, David
AU - DiPersio, John F.
PY - 2012/11/8
Y1 - 2012/11/8
N2 - The clinical goal of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is to minimize GVHD while maintaining GvL. Here, we show that interferon γ receptor-deficient (IFNγR-/-) 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 IFNγR-/- Tconv to GVHD target organs, especially the 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 although defective in suppressor function in vivo and that WT Tregs suppress GVHD in vivo only when allogeneic Tconv produce interferon γ (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.
AB - The clinical goal of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is to minimize GVHD while maintaining GvL. Here, we show that interferon γ receptor-deficient (IFNγR-/-) 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 IFNγR-/- Tconv to GVHD target organs, especially the 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 although defective in suppressor function in vivo and that WT Tregs suppress GVHD in vivo only when allogeneic Tconv produce interferon γ (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.
UR - http://www.scopus.com/inward/record.url?scp=84868606215&partnerID=8YFLogxK
U2 - 10.1182/blood-2012-01-403196
DO - 10.1182/blood-2012-01-403196
M3 - Article
C2 - 22972985
AN - SCOPUS:84868606215
SN - 0006-4971
VL - 120
SP - 4093
EP - 4103
JO - Blood
JF - Blood
IS - 19
ER -