STAT3 Signaling Induces the Differentiation of Human ICOS+ CD4 T Cells Helping B lymphocytes

Laure Ysebrant De Lendonck,Arnaud Marchant,Fouad Eddahri,Stanislas Goriely,Muriel Nguyen,Yves Delmarcelle,Oberdan Leo,Nathalie Labrecque

doi:10.1371/journal.pone.0071029

Laure Ysebrant De Lendonck, Arnaud Marchant + Show 6 more

Open Access

https://doi.org/10.1371/journal.pone.0071029

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Journal: PloS one	Publication Date: Jul 26, 2013
Citations: 49	License type: CC BY 4.0

Affiliation: Université Libre de Bruxelles

Abstract

The generation of high-affinity antibodies and the development of B cell memory are dependent on the help provided by CD4 T cells. Mouse studies indicate that STAT3 signaling in CD4 T cells promotes the acquisition of the B cell help function. However, the role of STAT3 in humans has been controversial. In this study, we show that IL-6 and other STAT3 activating cytokines (IL-21 and IL-27) induce the differentiation of CD4 T cells promoting antibody production by B cells. The acquisition of B cell stimulating properties by naive cord blood CD4 T cells required the STAT3-dependent expression of ICOS and IL-21. Gene reporter and ChIP experiments unambiguously demonstrated that upon IL-6 stimulation, STAT3 induces the transcription of the ICOS gene through direct recruitment to the proximal promoter region indicating that STAT3 acts in part through the direct activation of the ICOS gene.

Highlights

The generation of high affinity antibodies and the development of B cell memory are largely dependent on the help provided by CD4 T cells [1]
Supernatants from monocyte derived dendritic cells (moDCs) activated by either LPS or PolyI:C strongly enhanced the capacity of naive CD4 T cells to stimulate the production of IgG and IgM by B cells (Fig. 1A), indicating that soluble factors secreted by activated Dendritic cells (DCs) were sufficient to promote the differentiation of B cell activating CD4 T cells
These reports indicated that STAT3 activating cytokines either fail or have a limited capacity to induce the production of IL-21 by naive CD4 T cells [16,17]

Summary

Introduction

The generation of high affinity antibodies and the development of B cell memory are largely dependent on the help provided by CD4 T cells [1]. The B cell help function was long thought to be attributable to the Th2 subset. This notion was based on the ability of Th2 derived cytokines, in particular IL-4, to sustain B cell growth, differentiation and isotype switch [2,3]. Studies in mice indicate that STAT3 signaling induces the acquisition of B cell help properties by CD4 T cells, both in vitro and in vivo [12,13,14,15]. Two studies indicated that IL-12 promotes the acquisition of B cell help capacity by CD4 T cells through the activation of STAT4 and that STAT3 signaling may be less critical in this process [16,17]. Naive CD4 T cells from patients with STAT3 mutations causing autosomal dominant hyper-IgE syndrome (AD-HIES) were recently shown to be unable to acquire

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Conclusion