Alloreactive T cells play a critical role in eliminating hematopoietic malignant cells but are also the mediators of graft-versus-host disease (GVHD), a major complication that subverts the success of allogeneic hematopoietic stem cell transplantation (HSCT). However, induction of alloreactive T cells does not necessarily lead to GVHD. Here we report the development of a cellular programming approach to render alloreactive T cells incapable of causing severe GVHD in both major histocompatibility complex (MHC)-mismatched and MHC-identical but minor histocompatibility antigen-mismatched mouse models. We established a novel platform that produced δ-like ligand 4-positive dendritic cells (Dll4hiDCs) from murine bone marrow using Flt3 ligand and Toll-like receptor agonists. Upon allogeneic Dll4hi DC stimulation, CD4+ naïve T cells underwent effector differentiation and produced high levels of interferon γ (IFN-γ) and interleukin-17 in vitro, depending on Dll4 activation of Notch signaling. Following transfer, allogeneic Dll4hiDC-induced T cells were unable to mediate severe GVHD but preserved antileukemic activity, significantly improving the survival of leukemic mice undergoing allogeneic HSCT. This effect of Dll4hiDC-induced T cells was associated with their impaired expansion in GVHD target tissues. IFN-γ was important for Dll4hiDC programming to reduce GVHD toxicities of alloreactive T cells. Absence of T-cell IFN-γ led to improved survival and expansion of Dll4hiDC-induced CD4+ T cells in transplant recipients and caused lethal GVHD. Our findings demonstrate that Dll4hiDC programming can overcome GVHD toxicity of donor T cells and produce leukemia-reactive T cells for effective immunotherapy.
Bibliographical noteFunding Information:
The authors thank Warren Pear (University of Pennsylvania) and Ivan Maillard (University of Michigan) for kindly providing DN- MAML mice, and Marcel van den Brink (Memorial Sloan Kettering Cancer Center) for providing A20-TGL cells. This work was supported by a Damon Runyon-Rachleff Innovation Award (Yi Zhang), the American Cancer Society (Yi Zhang), the Department of Defense (Yi Zhang), and National Cancer Institute, National Institutes of Health (grants CA172106 [Yi Zhang], CA72669 [B.R.B.], and CA178202 [R.R.]).
© 2016 by The American Society of Hematology.