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

Kazuhiro Mochizuki, Lijun Meng, Izumi Mochizuki, Qing Tong, Shan He, Yongnian Liu, Janaki Purushe, Henry Fung, M. Raza Zaidi, Yanyun Zhang, Ran Reshef, Bruce R. Blazar, Hideo Yagita, Shin Mineishi, Yi Zhang

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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 (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.

Original languageEnglish (US)
Pages (from-to)3270-3280
Number of pages11
JournalBlood
Volume127
Issue number25
DOIs
StatePublished - Jun 23 2016

Bibliographical note

Funding 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.]).

Publisher Copyright:
© 2016 by The American Society of Hematology.

Fingerprint Dive into the research topics of 'Programming of donor T cells using allogeneic δ-like ligand 4-positive dendritic cells to reduce GVHD in mice'. Together they form a unique fingerprint.

Cite this