Cutting edge: circulating plasmablasts induce the differentiation of human T follicular helper cells via IL-6 production.

Konstantia-Maria Chavele,Michael R Ehrenstein,Eve Merry

doi:10.4049/jimmunol.1401190

Konstantia-Maria Chavele, Michael R Ehrenstein + Show 1 more

Open Access

https://doi.org/10.4049/jimmunol.1401190

Copy DOI

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.

Highlights

Specific targeting of IL-6 using tocilizumab therapy in patients with rheumatoid arthritis led to a significant reduction in circulating T follicular helper (Tfh) cell numbers and IL-21 production, which was correlated with reduced plasmablast formation
Bcl-6 was expressed at low levels in CUTTING EDGE: PLASMABLASTS PROMOTE HUMAN T FOLLICULAR HELPER CELLS
We sought to identify whether B cells promoted the formation of Tfh cells and found that removal of the former from PBMCs led to a significant reduction in Tfh cells (Fig. 1A), as well as Bcl-6 expression in the Tfh cell population, after stimulation with anti-CD3/CD28 (Fig. 1B), suggesting a role for B cells in the maintenance of this T cell lineage

Summary

Introduction

Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription 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. Plasmablasts were isolated from peripheral blood, according to their expression of CD38 and CD27 [5] (Supplemental Fig. 1D), and compared with naive B cells for their ability to expand Tfh cells.

Results

Conclusion