Context-Dependent Role for T-bet in T Follicular Helper Differentiation and Germinal Center Function following Viral Infection

Amania A. Sheikh, Lucy Cooper, Meiqi Feng, Fernando Souza-Fonseca-Guimaraes, Fanny Lafouresse, Brigette C. Duckworth, Nicholas D. Huntington, James J. Moon, Marc Pellegrini, Stephen L. Nutt, Gabrielle T. Belz, Kim L. Good-Jacobson, Joanna R. Groom

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

Abstract

Following infection, inflammatory cues upregulate core transcriptional programs to establish pathogen-specific protection. In viral infections, T follicular helper (TFH) cells express the prototypical T helper 1 transcription factor T-bet. Several studies have demonstrated essential but conflicting roles for T-bet in TFH biology. Understanding the basis of this controversy is crucial, as modulation of T-bet expression instructs TFH differentiation and ultimately protective antibody responses. Comparing influenza and LCMV viral infections, we demonstrate that the role of T-bet is contingent on the environmental setting of TFH differentiation, IL-2 signaling, and T cell competition. Furthermore, we demonstrate that T-bet expression by either TFH or GC B cells independently drives antibody isotype class switching. Specifically, T cell-specific loss of T-bet promotes IgG1, whereas B cell-specific loss of T-bet inhibits IgG2a/c switching. Combined, this work highlights that the context-dependent induction of T-bet instructs the development of protective, neutralizing antibodies following viral infection or vaccination. Shiekh et al. show that, in influenza and LCMV infections, the role of the transcription factor T-bet in TFH differentiation is contingent on environmental cues, IL-2 signaling, and T cell competition. Cell-specific T-bet expression independently drives antibody isotype class switching. Therefore T-bet instructs immune protection in a context-dependent manner.

Original languageEnglish
Pages (from-to)1758-1772
Number of pages15
JournalCell Reports
Volume28
Issue number7
DOIs
Publication statusPublished - 13 Aug 2019

Keywords

  • germinal center
  • influenza
  • isotope switching
  • T cell differentiation
  • T follicular helper
  • T helper 1
  • T-bet
  • transcriptional regulation
  • viral infection

Cite this

Sheikh, A. A., Cooper, L., Feng, M., Souza-Fonseca-Guimaraes, F., Lafouresse, F., Duckworth, B. C., ... Groom, J. R. (2019). Context-Dependent Role for T-bet in T Follicular Helper Differentiation and Germinal Center Function following Viral Infection. Cell Reports, 28(7), 1758-1772. https://doi.org/10.1016/j.celrep.2019.07.034
Sheikh, Amania A. ; Cooper, Lucy ; Feng, Meiqi ; Souza-Fonseca-Guimaraes, Fernando ; Lafouresse, Fanny ; Duckworth, Brigette C. ; Huntington, Nicholas D. ; Moon, James J. ; Pellegrini, Marc ; Nutt, Stephen L. ; Belz, Gabrielle T. ; Good-Jacobson, Kim L. ; Groom, Joanna R. / Context-Dependent Role for T-bet in T Follicular Helper Differentiation and Germinal Center Function following Viral Infection. In: Cell Reports. 2019 ; Vol. 28, No. 7. pp. 1758-1772.
@article{6678e3e3731f41a0bf5f2497b8c1084f,
title = "Context-Dependent Role for T-bet in T Follicular Helper Differentiation and Germinal Center Function following Viral Infection",
abstract = "Following infection, inflammatory cues upregulate core transcriptional programs to establish pathogen-specific protection. In viral infections, T follicular helper (TFH) cells express the prototypical T helper 1 transcription factor T-bet. Several studies have demonstrated essential but conflicting roles for T-bet in TFH biology. Understanding the basis of this controversy is crucial, as modulation of T-bet expression instructs TFH differentiation and ultimately protective antibody responses. Comparing influenza and LCMV viral infections, we demonstrate that the role of T-bet is contingent on the environmental setting of TFH differentiation, IL-2 signaling, and T cell competition. Furthermore, we demonstrate that T-bet expression by either TFH or GC B cells independently drives antibody isotype class switching. Specifically, T cell-specific loss of T-bet promotes IgG1, whereas B cell-specific loss of T-bet inhibits IgG2a/c switching. Combined, this work highlights that the context-dependent induction of T-bet instructs the development of protective, neutralizing antibodies following viral infection or vaccination. Shiekh et al. show that, in influenza and LCMV infections, the role of the transcription factor T-bet in TFH differentiation is contingent on environmental cues, IL-2 signaling, and T cell competition. Cell-specific T-bet expression independently drives antibody isotype class switching. Therefore T-bet instructs immune protection in a context-dependent manner.",
keywords = "germinal center, influenza, isotope switching, T cell differentiation, T follicular helper, T helper 1, T-bet, transcriptional regulation, viral infection",
author = "Sheikh, {Amania A.} and Lucy Cooper and Meiqi Feng and Fernando Souza-Fonseca-Guimaraes and Fanny Lafouresse and Duckworth, {Brigette C.} and Huntington, {Nicholas D.} and Moon, {James J.} and Marc Pellegrini and Nutt, {Stephen L.} and Belz, {Gabrielle T.} and Good-Jacobson, {Kim L.} and Groom, {Joanna R.}",
year = "2019",
month = "8",
day = "13",
doi = "10.1016/j.celrep.2019.07.034",
language = "English",
volume = "28",
pages = "1758--1772",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Elsevier",
number = "7",

}

Sheikh, AA, Cooper, L, Feng, M, Souza-Fonseca-Guimaraes, F, Lafouresse, F, Duckworth, BC, Huntington, ND, Moon, JJ, Pellegrini, M, Nutt, SL, Belz, GT, Good-Jacobson, KL & Groom, JR 2019, 'Context-Dependent Role for T-bet in T Follicular Helper Differentiation and Germinal Center Function following Viral Infection', Cell Reports, vol. 28, no. 7, pp. 1758-1772. https://doi.org/10.1016/j.celrep.2019.07.034

Context-Dependent Role for T-bet in T Follicular Helper Differentiation and Germinal Center Function following Viral Infection. / Sheikh, Amania A.; Cooper, Lucy; Feng, Meiqi; Souza-Fonseca-Guimaraes, Fernando; Lafouresse, Fanny; Duckworth, Brigette C.; Huntington, Nicholas D.; Moon, James J.; Pellegrini, Marc; Nutt, Stephen L.; Belz, Gabrielle T.; Good-Jacobson, Kim L.; Groom, Joanna R.

In: Cell Reports, Vol. 28, No. 7, 13.08.2019, p. 1758-1772.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Context-Dependent Role for T-bet in T Follicular Helper Differentiation and Germinal Center Function following Viral Infection

AU - Sheikh, Amania A.

AU - Cooper, Lucy

AU - Feng, Meiqi

AU - Souza-Fonseca-Guimaraes, Fernando

AU - Lafouresse, Fanny

AU - Duckworth, Brigette C.

AU - Huntington, Nicholas D.

AU - Moon, James J.

AU - Pellegrini, Marc

AU - Nutt, Stephen L.

AU - Belz, Gabrielle T.

AU - Good-Jacobson, Kim L.

AU - Groom, Joanna R.

PY - 2019/8/13

Y1 - 2019/8/13

N2 - Following infection, inflammatory cues upregulate core transcriptional programs to establish pathogen-specific protection. In viral infections, T follicular helper (TFH) cells express the prototypical T helper 1 transcription factor T-bet. Several studies have demonstrated essential but conflicting roles for T-bet in TFH biology. Understanding the basis of this controversy is crucial, as modulation of T-bet expression instructs TFH differentiation and ultimately protective antibody responses. Comparing influenza and LCMV viral infections, we demonstrate that the role of T-bet is contingent on the environmental setting of TFH differentiation, IL-2 signaling, and T cell competition. Furthermore, we demonstrate that T-bet expression by either TFH or GC B cells independently drives antibody isotype class switching. Specifically, T cell-specific loss of T-bet promotes IgG1, whereas B cell-specific loss of T-bet inhibits IgG2a/c switching. Combined, this work highlights that the context-dependent induction of T-bet instructs the development of protective, neutralizing antibodies following viral infection or vaccination. Shiekh et al. show that, in influenza and LCMV infections, the role of the transcription factor T-bet in TFH differentiation is contingent on environmental cues, IL-2 signaling, and T cell competition. Cell-specific T-bet expression independently drives antibody isotype class switching. Therefore T-bet instructs immune protection in a context-dependent manner.

AB - Following infection, inflammatory cues upregulate core transcriptional programs to establish pathogen-specific protection. In viral infections, T follicular helper (TFH) cells express the prototypical T helper 1 transcription factor T-bet. Several studies have demonstrated essential but conflicting roles for T-bet in TFH biology. Understanding the basis of this controversy is crucial, as modulation of T-bet expression instructs TFH differentiation and ultimately protective antibody responses. Comparing influenza and LCMV viral infections, we demonstrate that the role of T-bet is contingent on the environmental setting of TFH differentiation, IL-2 signaling, and T cell competition. Furthermore, we demonstrate that T-bet expression by either TFH or GC B cells independently drives antibody isotype class switching. Specifically, T cell-specific loss of T-bet promotes IgG1, whereas B cell-specific loss of T-bet inhibits IgG2a/c switching. Combined, this work highlights that the context-dependent induction of T-bet instructs the development of protective, neutralizing antibodies following viral infection or vaccination. Shiekh et al. show that, in influenza and LCMV infections, the role of the transcription factor T-bet in TFH differentiation is contingent on environmental cues, IL-2 signaling, and T cell competition. Cell-specific T-bet expression independently drives antibody isotype class switching. Therefore T-bet instructs immune protection in a context-dependent manner.

KW - germinal center

KW - influenza

KW - isotope switching

KW - T cell differentiation

KW - T follicular helper

KW - T helper 1

KW - T-bet

KW - transcriptional regulation

KW - viral infection

UR - http://www.scopus.com/inward/record.url?scp=85070199715&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2019.07.034

DO - 10.1016/j.celrep.2019.07.034

M3 - Article

VL - 28

SP - 1758

EP - 1772

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 7

ER -

Sheikh AA, Cooper L, Feng M, Souza-Fonseca-Guimaraes F, Lafouresse F, Duckworth BC et al. Context-Dependent Role for T-bet in T Follicular Helper Differentiation and Germinal Center Function following Viral Infection. Cell Reports. 2019 Aug 13;28(7):1758-1772. https://doi.org/10.1016/j.celrep.2019.07.034