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

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          Summary

          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 CD40L high iPS-T cells stimulated WT1-specific CTL priming, which eliminated WT1 peptide-expressing CML cells in vitro and in vivo. Thus, CD4 modification of CD40L high 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.

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          Highlights

          • iPSC-derived T cells have molecular similarity to group 1 innate lymphoid cells
          • iPSC-derived CD40L high T cell-adjuvants induce leukemia-specific CTLs via DCs

          Abstract

          Kaneko and colleagues describe the generation of CD4 + T helper clone-derived iPSCs and differentiation of the cells into T-lineage cells, which had molecular signatures and functional properties more consistent with group 1 innate lymphoid cells. CD4 transduction and CD40 ligand high population purification of the regenerated cells enhanced the antigen-specific adjuvant responses via dendritic cells in an antigen-specific manner.

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          Most cited references 28

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          T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions.

          Although in vivo priming of CD8+ cytotoxic T lymphocytes (CTLs) generally requires the participation of CD4+ T-helper lymphocytes, the nature of the 'help' provided to CTLs is unknown. One widely held view is that help for CTLs is mediated by cytokines produced by T-helper cells activated in proximity to the CTL precursor at the surface of an antigen-presenting cell (APC). An alternative theory is that, rather than being directly supplied to the CTL by the helper cell, help is delivered through activation of the APC, which can then prime the CTL directly. CD40 and its ligand, CD40L, may activate the APC to allow CTL priming. CD40L is expressed on the surface of activated CD4+ T-helper cells and is involved in their activation and in the development of their effector functions. Ligation of CD40 on the surface of APCs such as dendritic cells, macrophages and B cells greatly increases their antigen-presentation and co-stimulatory capacity. Here we report that signalling through CD40 can replace CD4+ T-helper cells in priming of helper-dependent CD8+ CTL responses. Blockade of CD40L inhibits CTL priming; this inhibition is overcome by signalling through CD40. CD40-CD40L interactions are therefore vital in the delivery of T-cell help for CTL priming.
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            A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell.

            To generate an immune response, antigen-specific T-helper and T-killer cells must find each other and, because they cannot detect each other's presence, they are brought together by an antigen-loaded dendritic cell that displays antigens to both. This three-cell interaction, however, seems nearly impossible because all three cell types are rare and migratory. Here we provide a potential solution to this conundrum. We found that the three cells need not meet simultaneously but that the helper cell can first engage and 'condition' the dendritic cell, which then becomes empowered to stimulate a killer cell. The first step (help) can be bypassed by modulation of the surface molecule CD40, or by viral infection of dendritic cells. These results may explain the long-standing paradoxical observation that responses to some viruses are helper-independent, and they evoke the possibility that dendritic cells may take on different functions in response to different conditioning signals.
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              CXCR3 in T cell function.

              CXCR3 is a chemokine receptor that is highly expressed on effector T cells and plays an important role in T cell trafficking and function. CXCR3 is rapidly induced on naïve cells following activation and preferentially remains highly expressed on Th1-type CD4(+) T cells and effector CD8(+) T cells. CXCR3 is activated by three interferon-inducible ligands CXCL9 (MIG), CXCL10 (IP-10) and CXCL11 (I-TAC). Early studies demonstrated a role for CXCR3 in the trafficking of Th1 and CD8 T cells to peripheral sites of Th1-type inflammation and the establishment of a Th1 amplification loop mediated by IFNγ and the IFNγ-inducible CXCR3 ligands. More recent studies have also suggested that CXCR3 plays a role in the migration of T cells in the microenvironment of the peripheral tissue and lymphoid compartment, facilitating the interaction of T cells with antigen presenting cells leading to the generation of effector and memory cells. Copyright © 2010 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Stem Cell Reports
                Stem Cell Reports
                Stem Cell Reports
                Elsevier
                2213-6711
                24 May 2018
                05 June 2018
                24 May 2018
                : 10
                : 6
                : 1935-1946
                Affiliations
                [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
                [2 ]Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
                [3 ]Division of Cancer Immunotherapy, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center (NCC), 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan
                [4 ]Division of Immunology, Aichi Cancer Center Research Institute (ACCRI), 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan
                [5 ]Key Laboratory of Cancer Center, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853, China
                [6 ]Department of Life Science Frontiers, CiRA, Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8501, Japan
                [7 ]Research Center for Stem Cell Engineering, National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Higashi, Tsukuba, Ibaraki 305-8561, Japan
                [8 ]Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan
                [9 ]Department of Cellular Oncology, Nagoya University Graduate School of Medicine, 65, Tsurumai-cho, Showa-ku, Nagoya 464-8603, Japan
                [10 ]National Hospital Organization Nagoya Medical Center, 4-1-1, Sannomaru, Naka-ku, Nagoya 460-0001, Japan
                Author notes
                []Corresponding author yuemura@ 123456east.ncc.go.jp
                [∗∗ ]Corresponding author kaneko.shin@ 123456cira.kyoto-u.ac.jp
                Article
                S2213-6711(18)30193-0
                10.1016/j.stemcr.2018.04.025
                5993651
                29805109
                © 2018 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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