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

10 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

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