title: Human B cells differentiate into granzyme B-secreting cytotoxic B lymphocytes upon incomplete T-cell help.
abstract: 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.
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Australia.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Hagn
authors.forename: Kai
authors.initials: K
authors.lastname: Sontheimer
authors.forename: Karen
authors.initials: K
authors.lastname: Dahlke
authors.forename: Sabine
authors.initials: S
authors.lastname: Brueggemann
authors.forename: Christof
authors.initials: C
authors.lastname: Kaltenmeier
authors.forename: Thamara
authors.initials: T
authors.lastname: Beyer
authors.forename: Stefanie
authors.initials: S
authors.lastname: Hofmann
authors.forename: Oleg
authors.initials: O
authors.lastname: Lunov
authors.forename: Thomas F E
authors.initials: TF
authors.lastname: Barth
authors.forename: Dorit
authors.initials: D
authors.lastname: Fabricius
authors.forename: Kyrylo
authors.initials: K
authors.lastname: Tron
authors.forename: Gerd Ulrich
authors.initials: GU
authors.lastname: Nienhaus
authors.forename: Thomas
authors.initials: T
authors.lastname: Simmet
authors.forename: Hubert
authors.initials: H
authors.lastname: Schrezenmeier
authors.forename: Bernd
authors.initials: B
authors.lastname: Jahrsdörfer
mesh_terms: D001402:B-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D023201:CD40 Ligand; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D053804:Granzymes / Q000378:metabolism*; D006801:Humans; D007111:Immunity, Cellular; D007376:Interleukin-2 / Q000494:pharmacology; D007378:Interleukins / Q000494:pharmacology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D000098546:Interleukin-21
chemical_list: D007376:Interleukin-2; D007378:Interleukins; D023201:CD40 Ligand; D053804:Granzymes; D000098546:Interleukin-21