TRANSPLANTATION Programming of donor T cells using allogeneic d -like ligand 4 – positive dendritic cells to reduce GVHD in mice

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 d -like ligand 4–positive dendritic cells (Dll4 hi DCs) from murine bone marrow using Flt3 ligand and Toll-like receptor agonists. Upon allogeneic Dll4 hi DC stimulation, CD4 1 na¨ıve T cells underwent effector differentiation and produced high levels of interferon g (IFN- g ) and interleukin-17 in vitro, depending on Dll4 activation of Notch signaling. Following transfer, allogeneic Dll4 hi DC-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 Dll4 hi DC-induced TcellswasassociatedwiththeirimpairedexpansioninGVHDtargettissues.IFN- g wasimportantforDll4 hi DCprogrammingtoreduce GVHD toxicities of alloreactive T cells. Absence of T-cell IFN- g led to improved survival and expansion of Dll4 hi DC-induced CD4 1 T cells in transplant recipients and caused lethal GVHD. Our findings demonstrate that Dll4 hi DC programming can overcome GVHD toxicity of donor T cells and produce leukemia-reactive T cells for effective immunotherapy. ( Blood . 2016;127(25):3270-3280)

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