Regulatory T Cells Restrain Interleukin-2- and Blimp-1-Dependent Acquisition of Cytotoxic Function by CD4 + T Cells.

Autor:	Śledzińska A; Cancer Immunology Unit, UCL Cancer Institute, University College London, London WC1E 6DD, UK; Research Department of Haematology, University College London, Cancer Institute, London WC1E 6DD, UK., Vila de Mucha M; Cancer Immunology Unit, UCL Cancer Institute, University College London, London WC1E 6DD, UK; Regulatory Genomics Research Group, UCL Cancer Institute, University College London, London WC1E 6DD, UK., Bergerhoff K; Cancer Immunology Unit, UCL Cancer Institute, University College London, London WC1E 6DD, UK; Research Department of Haematology, University College London, Cancer Institute, London WC1E 6DD, UK., Hotblack A; Research Department of Haematology, University College London, Cancer Institute, London WC1E 6DD, UK., Demane DF; Cancer Immunology Unit, UCL Cancer Institute, University College London, London WC1E 6DD, UK; Research Department of Haematology, University College London, Cancer Institute, London WC1E 6DD, UK., Ghorani E; Cancer Immunology Unit, UCL Cancer Institute, University College London, London WC1E 6DD, UK; Research Department of Haematology, University College London, Cancer Institute, London WC1E 6DD, UK., Akarca AU; Department of Cellular Pathology, University College London Hospital, London NW1 2BU, UK., Marzolini MAV; Cancer Immunology Unit, UCL Cancer Institute, University College London, London WC1E 6DD, UK; Research Department of Haematology, University College London, Cancer Institute, London WC1E 6DD, UK., Solomon I; Cancer Immunology Unit, UCL Cancer Institute, University College London, London WC1E 6DD, UK; Research Department of Haematology, University College London, Cancer Institute, London WC1E 6DD, UK., Vargas FA; Cancer Immunology Unit, UCL Cancer Institute, University College London, London WC1E 6DD, UK; Research Department of Haematology, University College London, Cancer Institute, London WC1E 6DD, UK., Pule M; Research Department of Haematology, University College London, Cancer Institute, London WC1E 6DD, UK., Ono M; Faculty of Natural Sciences, Department of Life Sciences, Imperial College London, London SW7 2BB, UK., Seddon B; Institute of Immunity and Transplantation, Department of Immunology, Royal Free Hospital, London NW3 2PF, UK., Kassiotis G; Retroviral Immunology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK., Ariyan CE; Memorial Sloan Kettering Center, 1275 York Avenue, New York, NY 10065, USA., Korn T; Department of Experimental Neuroimmunology, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany., Marafioti T; Department of Cellular Pathology, University College London Hospital, London NW1 2BU, UK., Lord GM; Faculty of Biology, Medicine and Health, University of Manchester, 46 Grafton Street, Manchester M13 9NT, UK., Stauss H; Institute of Immunity and Transplantation, Department of Immunology, Royal Free Hospital, London NW3 2PF, UK., Jenner RG; Regulatory Genomics Research Group, UCL Cancer Institute, University College London, London WC1E 6DD, UK., Peggs KS; Cancer Immunology Unit, UCL Cancer Institute, University College London, London WC1E 6DD, UK; Research Department of Haematology, University College London, Cancer Institute, London WC1E 6DD, UK. Electronic address: k.peggs@ucl.ac.uk., Quezada SA; Cancer Immunology Unit, UCL Cancer Institute, University College London, London WC1E 6DD, UK; Research Department of Haematology, University College London, Cancer Institute, London WC1E 6DD, UK. Electronic address: s.quezada@ucl.ac.uk.
Jazyk:	angličtina
Zdroj:	Immunity [Immunity] 2020 Jan 14; Vol. 52 (1), pp. 151-166.e6. Date of Electronic Publication: 2020 Jan 07.
DOI:	10.1016/j.immuni.2019.12.007
Abstrakt:	In addition to helper and regulatory potential, CD4 + T cells also acquire cytotoxic activity marked by granzyme B (GzmB) expression and the ability to promote rejection of established tumors. Here, we examined the molecular and cellular mechanisms underpinning the differentiation of cytotoxic CD4 + T cells following immunotherapy. CD4 + transfer into lymphodepleted animals or regulatory T (Treg) cell depletion promoted GzmB expression by tumor-infiltrating CD4 + , and this was prevented by interleukin-2 (IL-2) neutralization. Transcriptional analysis revealed a polyfunctional helper and cytotoxic phenotype characterized by the expression of the transcription factors T-bet and Blimp-1. While T-bet ablation restricted interferon-γ (IFN-γ) production, loss of Blimp-1 prevented GzmB expression in response to IL-2, suggesting two independent programs required for polyfunctionality of tumor-reactive CD4 + T cells. Our findings underscore the role of Treg cells, IL-2, and Blimp-1 in controlling the differentiation of cytotoxic CD4 + T cells and offer a pathway to enhancement of anti-tumor activity through their manipulation. (Copyright © 2019 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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