Cutting Edge: Circulating Plasmablasts Induce the Differentiation of Human T Follicular Helper Cells via IL-6 Production

• Published in: The Journal of immunology (1950) Vol. 194; no. 6; pp. 2482 - 2485
• Main Authors: Chavele, Konstantia-Maria, Merry, Eve, Ehrenstein, Michael R
• Format: Journal Article
• Language: English
• Published: England AAI 15.03.2015
• Subjects: Antibodies, Monoclonal, Humanized - immunology; Antibodies, Monoclonal, Humanized - therapeutic use; Antigens, CD19 - immunology; Antigens, CD19 - metabolism; Arthritis, Rheumatoid - blood; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - immunology; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cell Differentiation - immunology; Cell Proliferation; Cells, Cultured; Coculture Techniques; Cutting Edge; DNA-Binding Proteins - immunology; DNA-Binding Proteins - metabolism; Flow Cytometry; Humans; Inducible T-Cell Co-Stimulator Protein - immunology; Inducible T-Cell Co-Stimulator Protein - metabolism; Interleukin-21; Interleukin-6 - immunology; Interleukin-6 - metabolism; Interleukins - immunology; Interleukins - metabolism; Plasma Cells - immunology; Plasma Cells - metabolism; Proto-Oncogene Proteins c-bcl-6; Receptors, CXCR5 - immunology; Receptors, CXCR5 - metabolism; T-Lymphocytes, Helper-Inducer - immunology; T-Lymphocytes, Helper-Inducer - metabolism
• ISSN: 0022-1767; 1550-6606; 1550-6606
• DOI: 10.4049/jimmunol.1401190

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.