Chemokine receptors are required for effector T cell trafficking to GVHD tissues but not to bone marrow.

In allogeneic hematopoietic stem cell transplantation (alloSCT), alloreactive donor T cells mediate the graft-versus-leukemia (GVL) effect but also attack nonhematopoietic tissues causing graft-versus-host disease (GVHD). Reducing alloreactive T cell trafficking to GVHD target tissues while allowing their access to bone marrow (BM) and spleen, major sites of malignant hematopoiesis, is a rational strategy for reducing the GVHD risk when using alloreactive T cells as a therapeutic. Here we show that effector T cell (Teff) entry into BM and spleen in unmanipulated mice and in mice transplanted without alloreactive T cells is augmented by pertussis toxin-sensitive (PTX) chemokine receptor signaling. However, unexpectedly, in the presence of a GVH response, chemokines no longer draw T cells into BM and spleen but remain critical for their recruitment to GVHD target tissues. Consistent with this, PTX-treated Teff cells were as efficacious as untreated T cells in killing leukemia cells in BM and spleen in mice with a concurrent GVHD response. These results suggest a strategy to improve the safety of alloreactive T cell therapeutics in treating leukemias in the context of an alloSCT.