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Stem Cell Reports. 2018 Jun 5;10(6):1935-1946. doi: 10.1016/j.stemcr.2018.04.025. Epub 2018 May 24.

Generation of TCR-Expressing Innate Lymphoid-like Helper Cells that Induce Cytotoxic T Cell-Mediated Anti-leukemic Cell Response.

Author information

1
Shin Kaneko Laboratory, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8501, Japan; Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan; Division of Immunology, Aichi Cancer Center Research Institute (ACCRI), 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan.
2
Division of Cancer Immunotherapy, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center (NCC), 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan; Division of Immunology, Aichi Cancer Center Research Institute (ACCRI), 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan. Electronic address: yuemura@east.ncc.go.jp.
3
Division of Cancer Immunotherapy, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center (NCC), 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan; Division of Immunology, Aichi Cancer Center Research Institute (ACCRI), 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan.
4
Shin Kaneko Laboratory, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8501, Japan.
5
Division of Immunology, Aichi Cancer Center Research Institute (ACCRI), 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan.
6
Division of Immunology, Aichi Cancer Center Research Institute (ACCRI), 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan; Key Laboratory of Cancer Center, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853, China.
7
Department of Life Science Frontiers, CiRA, Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8501, Japan.
8
Research Center for Stem Cell Engineering, National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Higashi, Tsukuba, Ibaraki 305-8561, Japan.
9
Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
10
Division of Immunology, Aichi Cancer Center Research Institute (ACCRI), 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan; Department of Cellular Oncology, Nagoya University Graduate School of Medicine, 65, Tsurumai-cho, Showa-ku, Nagoya 464-8603, Japan.
11
Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
12
National Hospital Organization Nagoya Medical Center, 4-1-1, Sannomaru, Naka-ku, Nagoya 460-0001, Japan.
13
Shin Kaneko Laboratory, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: kaneko.shin@cira.kyoto-u.ac.jp.

Abstract

CD4+ T helper (Th) cell activation is essential for inducing cytotoxic T lymphocyte (CTL) responses against malignancy. We reprogrammed a Th clone specific for chronic myelogenous leukemia (CML)-derived b3a2 peptide to pluripotency and re-differentiated the cells into original TCR-expressing T-lineage cells (iPS-T cells) with gene expression patterns resembling those of group 1 innate lymphoid cells. CD4 gene transduction into iPS-T cells enhanced b3a2 peptide-specific responses via b3a2 peptide-specific TCR. iPS-T cells upregulated CD40 ligand (CD40L) expression in response to interleukin-2 and interleukin-15. In the presence of Wilms tumor 1 (WT1) peptide, antigen-specific dendritic cells (DCs) conditioned by CD4-modified CD40Lhigh iPS-T cells stimulated WT1-specific CTL priming, which eliminated WT1 peptide-expressing CML cells in vitro and in vivo. Thus, CD4 modification of CD40Lhigh iPS-T cells generates innate lymphoid helper-like cells inducing bcr-abl-specific TCR signaling that mediates effectiveanti-leukemic CTL responses via DC maturation, showing potential for adjuvant immunotherapy against leukemia.

KEYWORDS:

CD40L; DC activation; T cell differentiation; bcr-abl; chronic myeloid leukemia; iPSCs; immuno-adjuvant function; immunotherapy; innate lymphoid cells

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