Work

Interruption of the IFNγR/CXCR3 Axis Results in Altered T Cell Trafficking in Vivo and Abrogation of GVHD While Maintaining a Robust GVL Response

Year: 2012

Type: article

Abstract: The goal of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is to minimize graft-versus-host disease (GvHD) while maintaining a beneficial graft-versus-leukemia (GvL) effect. This can be achieved by infusing regulatory T cells (Tregs) which suppress GvHD but have only limited effects on GvL. Unfortunately, Tregs exist in low frequency in the peripheral blood, are costly to purify and expand, and after expansion are difficult to isolate due to the lack of cell surface markers. Thus, alternative therapeutic approaches are needed. Using an MHC-mismatched GvHD model, B6 (H-2b) → Balb/c (H-2d), we demonstrated that infusion of IFNγR deficient (IFNγR-/-) allogeneic donor T cells induced significantly less GvHD, compared to WT T cells, as determined by survival (74% vs. 0%; p = 0.0004), weight loss and percentages of B220+ B cells (12.4% vs. 3.8%; p = 0.0205), CD3+ T cells (14.3% vs. 4.3%; p = 0.0025) in blood. Of note was that the IFNγR-/- donor T cells induced a robust GvL effect in both systemic leukemia and solid tumor models using luciferase-expressing A20 cells derived from Balb/c. We found that IFNγR-/- T cells responded normally to allogeneic antigens in vitro, based on mixed lymphocyte reactions, and expressed similar levels of granzyme B, compared to WT T cells. Using bioluminescence imaging (BLI) and luciferase-transduced WT and IFNγR-/- T cells, we observed that IFNγR-/- T cells trafficked primarily to the spleen while WT T cells trafficked to gastrointestinal tract and lymph nodes, which are major GvHD target organs. These findings suggest that the reduced GvHD was not due to reduced function, altered subsets or relative deficiency of allogeneic donor T cells but from an alteration of in vivo trafficking of IFNγR-/- T cells compared to WT T cells. We further demonstrated that the IFNγR-mediated signaling in alloreactive donor T cells was required for expression of CXCR3 which has been implicated in trafficking of T cells to areas of inflammation and target organs, commonly known to be the sites of GvHD. In addition, overexpression of CXCR3 in IFNγR-/- T cells rescued the GvHD-inducing function of IFNγR-/- T cells. CXCR3-/- T cells and pharmacological approaches using inhibitors of IFNγR signaling recapitulated the anti-GvHD (and pro-GvL) effects seen in IFNγR-/- T cells after allo-HSCT. Thus, the IFNγR-CXCR3 axis represents a promising therapeutic target for future efforts to mitigate GvHD while maintaining GvL after allo-HSCT.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.bbmt.2011.12.408