Cutting edge: circulating plasmablasts induce the differentiation of human T follicular helper cells via IL-6 production.
Bottom Line: B cells require CD4(+) T follicular helper (Tfh) cells to progress through the germinal center and provide protective Ab responses.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.
Affiliation: Centre for Rheumatology, Division of Medicine, University College London, London WC1E 6JF, United Kingdom.Show MeSH
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Mentions: We next assessed whether circulating plasmablasts possessed the capacity to induce the differentiation of Tfh cells from naive T cells. Thus, plasmablasts, naive and memory B cells, and monocytes were isolated and added to naive T cells in the presence of anti-CD3/CD28. Plasmablasts were the most potent inducers of Tfh cell differentiation (Fig. 2A). Tfh cells induced in the presence of plasmablasts expressed high levels of PD-1 (Supplemental Fig. 1E) and Bcl-6 (Fig. 2B). In addition, plasmablast-induced Tfh cells secreted significantly more IL-21 compared with naive B cell–induced Tfh cells (Fig. 2C). Although naive B cells possessed some ability to induce Tfh cell differentiation, this could be explained, in part, by the formation of plasmablasts from naive B cells during the culture (Supplemental Fig. 1F). Indeed, the percentage of Tfh cells correlated with the numbers of plasmablasts present in these “naive B cell” cultures (Supplemental Fig. 1G). This finding suggests that the induction of Tfh cell differentiation was due, in part, to newly formed plasmablasts from naive B cells, although other mechanisms may contribute, given that monocytes can increase the number of Tfh cells above that seen with naive T cells alone. To support this finding we cocultured different ratios of naive CD4+ T cells/plasmablasts and assessed the induction of Tfh cell differentiation. The ratio of plasmablasts/naive CD4+ T cells in these cultures was directly proportional to Tfh cell differentiation (Supplemental Fig. 1H). To ascertain whether the differentiated Tfh cells were functional, T cells were repurified after 4 d of culture with plasmablasts and incubated with freshly isolated autologous naive B cells or memory B cells, as previously described (6). Plasmablast-induced Tfh cells provided enhanced B cell help and supported naive B cells and memory B cells to produce significantly more IgM (Fig. 2D) and IgG (Fig. 2E), respectively, compared with T cells that had not been exposed to plasmablasts. To our knowledge, our results show for the first time that human plasmablasts are potent inducers of Tfh cell differentiation. Of relevance, murine plasma cells were shown to inhibit, rather than promote, Tfh cell formation (7). This discrepancy may reflect differences between plasma cells and circulating plasmablasts, or it could be due to differential regulation of Tfh cells in mice and humans.
Affiliation: Centre for Rheumatology, Division of Medicine, University College London, London WC1E 6JF, United Kingdom.