Human B cells differentiate into granzyme B-secreting cytotoxic B lymphocytes upon incomplete T-cell help
Magdalena Hagn
Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Australia
Search for more papers by this authorKai Sontheimer
Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany
These authors contributed equally to this work.
Search for more papers by this authorKaren Dahlke
Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany
These authors contributed equally to this work.
Search for more papers by this authorSabine Brueggemann
Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany
Search for more papers by this authorChristof Kaltenmeier
Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany
Search for more papers by this authorThamara Beyer
Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service Baden-Württemberg-Hessen and Institute of Transfusion Medicine, University of Ulm, Ulm, Germany
Search for more papers by this authorStefanie Hofmann
Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service Baden-Württemberg-Hessen and Institute of Transfusion Medicine, University of Ulm, Ulm, Germany
Search for more papers by this authorOleg Lunov
Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany
Search for more papers by this authorThomas FE Barth
Institute of Pathology, Ulm University, Ulm, Germany
Search for more papers by this authorDorit Fabricius
Department of Pediatrics, Ulm University, Ulm, Germany
Search for more papers by this authorKyrylo Tron
Institute of Biophysics, Ulm University, Ulm, Germany
Search for more papers by this authorGerd Ulrich Nienhaus
Institute of Biophysics, Ulm University, Ulm, Germany
Institute of Applied Physics and Center for Functional Nanostructures (CFN), Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany
Search for more papers by this authorThomas Simmet
Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany
Search for more papers by this authorHubert Schrezenmeier
Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service Baden-Württemberg-Hessen and Institute of Transfusion Medicine, University of Ulm, Ulm, Germany
Search for more papers by this authorCorresponding Author
Bernd Jahrsdörfer
Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service Baden-Württemberg-Hessen and Institute of Transfusion Medicine, University of Ulm, Ulm, Germany
Dr B Jahrsdörfer, Laboratory of Tumor and B Cell Immunology, Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, Ulm University, Helmholtzstrasse 10, 89081 Ulm, Germany. E-mail: [email protected]Search for more papers by this authorMagdalena Hagn
Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Australia
Search for more papers by this authorKai Sontheimer
Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany
These authors contributed equally to this work.
Search for more papers by this authorKaren Dahlke
Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany
These authors contributed equally to this work.
Search for more papers by this authorSabine Brueggemann
Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany
Search for more papers by this authorChristof Kaltenmeier
Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany
Search for more papers by this authorThamara Beyer
Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service Baden-Württemberg-Hessen and Institute of Transfusion Medicine, University of Ulm, Ulm, Germany
Search for more papers by this authorStefanie Hofmann
Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service Baden-Württemberg-Hessen and Institute of Transfusion Medicine, University of Ulm, Ulm, Germany
Search for more papers by this authorOleg Lunov
Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany
Search for more papers by this authorThomas FE Barth
Institute of Pathology, Ulm University, Ulm, Germany
Search for more papers by this authorDorit Fabricius
Department of Pediatrics, Ulm University, Ulm, Germany
Search for more papers by this authorKyrylo Tron
Institute of Biophysics, Ulm University, Ulm, Germany
Search for more papers by this authorGerd Ulrich Nienhaus
Institute of Biophysics, Ulm University, Ulm, Germany
Institute of Applied Physics and Center for Functional Nanostructures (CFN), Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany
Search for more papers by this authorThomas Simmet
Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany
Search for more papers by this authorHubert Schrezenmeier
Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service Baden-Württemberg-Hessen and Institute of Transfusion Medicine, University of Ulm, Ulm, Germany
Search for more papers by this authorCorresponding Author
Bernd Jahrsdörfer
Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service Baden-Württemberg-Hessen and Institute of Transfusion Medicine, University of Ulm, Ulm, Germany
Dr B Jahrsdörfer, Laboratory of Tumor and B Cell Immunology, Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, Ulm University, Helmholtzstrasse 10, 89081 Ulm, Germany. E-mail: [email protected]Search for more papers by this authorAbstract
Recently, CD4+ T helper cells were shown to induce differentiation of human B cells into plasma cells by expressing interleukin (IL-)21 and CD40 ligand (CD40L). In the present study we show, that in the absence of CD40L, CD4+ T cell-derived IL-21 induces differentiation of B cells into granzyme B (GzmB)-secreting cytotoxic cells. Using fluorescence-activated cell sorting (FACS) analysis, ELISpot and confocal microscopy, we demonstrate that CD4+ T cells, activated via their T-cell receptor without co-stimulation, can produce IL-21, but do not express CD40L and rapidly induce GzmB in co-cultured B cells in an IL-21 receptor-dependent manner. Of note, we confirmed these results with recombinant reagents, highlighting that CD40L suppresses IL-21-induced GzmB induction in B cells in a dose-dependent manner. Surprisingly, although GzmB-secreting B cells did not express perforin, they were able to transfer active GzmB to tumor cell lines, thereby effectively inducing apoptosis. In contrast, no cytotoxic effects were found when effector B cells were activated with IL-2 instead of IL-21 or when target cells were cultured with IL-21 alone. Our findings suggest GzmB+ cytotoxic B cells may have a role in early cellular immune responses including tumor immunosurveillance, before fully activated, antigen-specific cytotoxic T cells are on the spot. CD40 ligand determines whether IL-21 induces differentiation of B cells into plasma cells or into granzyme B-secreting cytotoxic cells.
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