Jelle de Wit1, Tineke Jorritsma1, Mateusz Makuch1, Ester B M Remmerswaal2, Hanny Klaasse Bos1, Yuri Souwer1, Jacques Neefjes3, Ineke J M ten Berge2, S Marieke van Ham4. 1. Department of Immunopathology, Sanquin Blood Supply, Division of Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 2. Renal Transplant Unit, Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 3. Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. 4. Department of Immunopathology, Sanquin Blood Supply, Division of Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: m.vanham@sanquin.nl.
Abstract
BACKGROUND: B cells mediate humoral immunity against pathogens but also direct CD4(+) T-cell responses. Recent plasticity studies in mice have challenged the concept of strict fate commitment during CD4(+) T-cell differentiation into distinct subsets. OBJECTIVE: We sought to elucidate the contribution of human antigen-primed B cells in CD4(+) T-cell responses that support humoral immunity. METHODS: CD4(+) T-cell differentiation by primary human B cells was investigated in in vitro cocultures by using tetanus toxoid and Salmonella species as antigen models. T-cell differentiation was assessed by using intracellular cytokines and subset-specific transcription factors and markers. IgM and IgG formation was analyzed by means of ELISA. RESULTS: Human B cells, but not dendritic cells, induce prominent and stable coexpression of TH1 and follicular helper T (TFH) cell characteristics during priming and on antigen recall. TH1/TFH cells coexpress the TH1 and TFH effector cytokines IFN-γ and IL-21 and the TFH marker CXCR5, demonstrating that the coexpressed TH1 and TFH subset-specifying transcription factors T-box transcription factor (T-bet) and B cell lymphoma 6 are both functionally active. B cell-derived IL-6 and IL-12 controlled respective expression of IL-21 and IFN-γ, with IL-21 being key for humoral immunity. CONCLUSION: Human B cells exploit CD4(+) T-cell plasticity to create flexibility in the effector T-cell response. Induction of a T-cell subset coexpressing IL-21 and IFN-γ might combine IL-21-mediated T-cell aid for antibody production while maintaining TH1 cytokine expression to support other cellular immune defenses.
BACKGROUND: B cells mediate humoral immunity against pathogens but also direct CD4(+) T-cell responses. Recent plasticity studies in mice have challenged the concept of strict fate commitment during CD4(+) T-cell differentiation into distinct subsets. OBJECTIVE: We sought to elucidate the contribution of human antigen-primed B cells in CD4(+) T-cell responses that support humoral immunity. METHODS: CD4(+) T-cell differentiation by primary human B cells was investigated in in vitro cocultures by using tetanus toxoid and Salmonella species as antigen models. T-cell differentiation was assessed by using intracellular cytokines and subset-specific transcription factors and markers. IgM and IgG formation was analyzed by means of ELISA. RESULTS:Human B cells, but not dendritic cells, induce prominent and stable coexpression of TH1 and follicular helper T (TFH) cell characteristics during priming and on antigen recall. TH1/TFH cells coexpress the TH1 and TFH effector cytokines IFN-γ and IL-21 and the TFH marker CXCR5, demonstrating that the coexpressed TH1 and TFH subset-specifying transcription factors T-box transcription factor (T-bet) and B cell lymphoma 6 are both functionally active. B cell-derived IL-6 and IL-12 controlled respective expression of IL-21 and IFN-γ, with IL-21 being key for humoral immunity. CONCLUSION:Human B cells exploit CD4(+) T-cell plasticity to create flexibility in the effector T-cell response. Induction of a T-cell subset coexpressing IL-21 and IFN-γ might combine IL-21-mediated T-cell aid for antibody production while maintaining TH1 cytokine expression to support other cellular immune defenses.
Authors: Willem J du Plessis; Léanie Kleynhans; Nelita du Plessis; Kim Stanley; Stephanus T Malherbe; Elizna Maasdorp; Katharina Ronacher; Novel N Chegou; Gerhard Walzl; Andre G Loxton Journal: PLoS One Date: 2016-04-06 Impact factor: 3.240
Authors: Niels J M Verstegen; Peter-Paul A Unger; Julia Z Walker; Benoit P Nicolet; Tineke Jorritsma; Jos van Rijssel; Robbert M Spaapen; Jelle de Wit; Jaap D van Buul; Anja Ten Brinke; S Marieke van Ham Journal: Front Immunol Date: 2019-03-13 Impact factor: 7.561