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.
Copyright © 2015 The Authors.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antibodies, Monoclonal, Humanized / immunology
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Antibodies, Monoclonal, Humanized / therapeutic use
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Antigens, CD19 / immunology
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Antigens, CD19 / metabolism
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Arthritis, Rheumatoid / blood
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Arthritis, Rheumatoid / drug therapy
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Arthritis, Rheumatoid / immunology
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B-Lymphocytes / immunology
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B-Lymphocytes / metabolism
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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Cell Differentiation / immunology*
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Cell Proliferation
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Cells, Cultured
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Coculture Techniques
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DNA-Binding Proteins / immunology
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DNA-Binding Proteins / metabolism
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Flow Cytometry
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Humans
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Inducible T-Cell Co-Stimulator Protein / immunology
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Inducible T-Cell Co-Stimulator Protein / metabolism
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Interleukin-6 / immunology*
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Interleukin-6 / metabolism
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Interleukins / immunology
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Interleukins / metabolism
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Plasma Cells / immunology*
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Plasma Cells / metabolism
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Proto-Oncogene Proteins c-bcl-6
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Receptors, CXCR5 / immunology
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Receptors, CXCR5 / metabolism
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T-Lymphocytes, Helper-Inducer / immunology*
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T-Lymphocytes, Helper-Inducer / metabolism
Substances
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Antibodies, Monoclonal, Humanized
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Antigens, CD19
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BCL6 protein, human
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CXCR5 protein, human
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DNA-Binding Proteins
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ICOS protein, human
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Inducible T-Cell Co-Stimulator Protein
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Interleukin-6
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Interleukins
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Proto-Oncogene Proteins c-bcl-6
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Receptors, CXCR5
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tocilizumab
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interleukin-21