title: Cutting edge: circulating plasmablasts induce the differentiation of human T follicular helper cells via IL-6 production.
abstract: B cells require CD4(+) T follicular helper (Tfh) cells to progress through the germinal center and provide protective Ab responses. In this article, we reveal a reciprocal interaction whereby circulating human plasmablasts are potent inducers of the Tfh cell-differentiation program, including the expression of their key transcription factor Bcl-6. The markedly increased propensity of plasmablasts, compared with naive B cells, to induce Tfh cell differentiation was due to their increased production of IL-6. Specific targeting of IL-6 using tocilizumab therapy in patients with rheumatoid arthritis led to a significant reduction in circulating Tfh cell numbers and IL-21 production, which was correlated with reduced plasmablast formation. Our data uncover a positive-feedback loop between circulating plasmablasts and Tfh cells that could sustain autoimmunity and spread Ab-driven inflammation to unaffected sites; this represents an important therapeutic target, as well as reveals a novel mechanism of action for tocilizumab.
authors: Centre for Rheumatology, Division of Medicine, University College London, London WC1E 6JF, United Kingdom.
authors: Konstantia-Maria
authors: KM
authors: Chavele
authors: Centre for Rheumatology, Division of Medicine, University College London, London WC1E 6JF, United Kingdom.
authors: Eve
authors: E
authors: Merry
authors: Centre for Rheumatology, Division of Medicine, University College London, London WC1E 6JF, United Kingdom m.ehrenstein@ucl.ac.uk.
authors: Michael R
authors: MR
authors: Ehrenstein
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology / Q000627:therapeutic use; D018941:Antigens, CD19 / Q000276:immunology / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology* / Q000378:metabolism; D007378:Interleukins / Q000276:immunology / Q000378:metabolism; D010950:Plasma Cells / Q000276:immunology* / Q000378:metabolism; D051560:Proto-Oncogene Proteins c-bcl-6; D054380:Receptors, CXCR5 / Q000276:immunology / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism; D000098546:Interleukin-21
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018941:Antigens, CD19; C084103:BCL6 protein, human; C095085:CXCR5 protein, human; D004268:DNA-Binding Proteins; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein; D015850:Interleukin-6; D007378:Interleukins; D051560:Proto-Oncogene Proteins c-bcl-6; D054380:Receptors, CXCR5; C502936:tocilizumab; D000098546:Interleukin-21