title: Programming of donor T cells using allogeneic δ-like ligand 4-positive dendritic cells to reduce GVHD in mice.
abstract: 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 (Dll4(hi)DCs) from murine bone marrow using Flt3 ligand and Toll-like receptor agonists. Upon allogeneic Dll4(hi)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 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 T cells was associated with their impaired expansion in GVHD target tissues. IFN-γ was important for Dll4(hi)DC programming to reduce GVHD toxicities of alloreactive T cells. Absence of T-cell IFN-γ led to improved survival and expansion of Dll4(hi)DC-induced CD4(+) 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.
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI;
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Mochizuki
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA; Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China;
authors.forename: Lijun
authors.initials: L
authors.lastname: Meng
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI;
authors.forename: Izumi
authors.initials: I
authors.lastname: Mochizuki
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA;
authors.forename: Qing
authors.initials: Q
authors.lastname: Tong
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA;
authors.forename: Shan
authors.initials: S
authors.lastname: He
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA;
authors.forename: Yongnian
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Microbiology and Immunology, Temple University, Philadelphia, PA;
authors.forename: Janaki
authors.initials: J
authors.lastname: Purushe
authors.affiliation: Department of Hematology/Oncology, Fox Chase Cancer Center, Temple Health, Philadelphia, PA;
authors.forename: Henry
authors.initials: H
authors.lastname: Fung
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA;
authors.forename: M Raza
authors.initials: MR
authors.lastname: Zaidi
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China;
authors.forename: Yanyun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;
authors.forename: Ran
authors.initials: R
authors.lastname: Reshef
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Pediatrics and Masonic Cancer Center, University of Minnesota, Minneapolis, MN;
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.affiliation: Department of Immunology, School of Medicine, Juntendo University, Tokyo, Japan; and.
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.affiliation: Department of Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Shin
authors.initials: S
authors.lastname: Mineishi
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA; Department of Microbiology and Immunology, Temple University, Philadelphia, PA;
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D065150:Cellular Reprogramming; D000067470:Cellular Reprogramming Techniques / Q000379:methods*; D003713:Dendritic Cells / Q000378:metabolism* / Q000502:physiology; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007938:Leukemia / Q000276:immunology / Q000628:therapy; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000276:immunology*; D014019:Tissue Donors; D014184:Transplantation, Homologous
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C064045:delta protein