IL-12 receptor β1 deficiency alters in vivo T follicular helper cell response in humans

Nathalie Schmitt,Jacinta Bustamante,Laure Bourdery,Salah Eddine Bentebibel,Stephanie Boisson-Dupuis,Fran Hamlin,Mau V Tran,Derek Blankenship,Virginia Pascual,Daniel A Savino,Jacques Banchereau,Jean-Laurent Casanova,Hideki Ueno

doi:10.1182/blood-2012-08-448902

Nathalie Schmitt, Jacinta Bustamante + Show 11 more

Open Access

https://doi.org/10.1182/blood-2012-08-448902

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Abstract

AbstractAntibody responses represent a key immune protection mechanism. T follicular helper (Tfh) cells are the major CD4+ T-cell subset that provides help to B cells to generate an antibody response. Tfh cells together with B cells form germinal centers (GCs), the site where high-affinity B cells are selected and differentiate into either memory B cells or long-lived plasma cells. We show here that interleukin-12 receptor β1 (IL-12Rβ1)–mediated signaling is important for in vivo Tfh response in humans. Although not prone to B cell-deficient–associated infections, subjects lacking functional IL-12Rβ1, a receptor for IL-12 and IL-23, displayed substantially less circulating memory Tfh and memory B cells than control subjects. GC formation in lymph nodes was also impaired in IL-12Rβ1–deficient subjects. Consistently, the avidity of tetanus toxoid–specific serum antibodies was substantially lower in these subjects than in age-matched controls. Tfh cells in tonsils from control individuals displayed the active form of signal transducer and activator of transcription 4 (STAT4), demonstrating that IL-12 is also acting on Tfh cells in GCs. Thus, our study shows that the IL-12–STAT4 axis is associated with the development and the functions of Tfh cells in vivo in humans.

Highlights

T follicular helper (Tfh) cells are essential for the generation of highaffinity memory B cells through the germinal center (GC) reaction.[1,2,3] Tfh cells express the chemokine (C-X-C) receptor 5 (CXCR5),[4,5,6,7] which guides their migration into B-cell follicles
Previous in vitro studies have shown that IL-12 induces human naıve CD41 T cells to express several molecules expressed by Tfh cells, such as IL-21, CXCR5, Inducible costimulator (ICOS), and B-cell lymphoma 6 (Bcl-6).18,26 To determine whether IL-12 is more potent than other cytokines in the induction of multiple Tfh-associated molecules, human naıve CD41 T cells were stimulated for 3 days by CD3 and CD28 monoclonal antibodies (mAbs)-coated beads in the presence of IL-12, IL-23, IL-6, IL-21, IL-10, and IL-27
Our present study provides in vivo evidence that IL-12Rb1–mediated signaling is involved in human Tfh reactions

Summary

Introduction

T follicular helper (Tfh) cells are essential for the generation of highaffinity memory B cells through the germinal center (GC) reaction.[1,2,3] Tfh cells express the chemokine (C-X-C) receptor 5 (CXCR5),[4,5,6,7] which guides their migration into B-cell follicles. Tonsillar Tfh cells express the transcription repressor B-cell lymphoma 6 (Bcl-6) at higher levels than any other CD41 T-cell subsets.[7,16,17,18] Mouse studies indicate that Bcl-6 is critical for Tfh cell generation in vivo, whereas Blimp-1, the transcription repressor that suppresses Bcl-6 function, inhibits their generation.[19,20,21] In addition to GC response, CD41 T cells provide help to B cells at extrafollicular sites and induce their differentiation into plasma cells that contribute to the early generation of specific antibodies after antigen challenge.[22] Extrafollicular helper cells appear to share the developmental mechanisms, phenotypes, and functional properties with Tfh cells.[16,23,24,25]

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