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

Cell Rep. 2019 Aug 13;28(7):1758-1772.e4. doi: 10.1016/j.celrep.2019.07.034.


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.

Keywords: T cell differentiation; T follicular helper; T helper 1; T-bet; germinal center; influenza; isotope switching; transcriptional regulation; viral infection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Viral / immunology
  • Antibody Formation / immunology*
  • Arenaviridae Infections / immunology
  • Arenaviridae Infections / metabolism
  • Arenaviridae Infections / virology
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / virology
  • Cell Differentiation*
  • Female
  • Germinal Center / immunology*
  • Germinal Center / metabolism
  • Germinal Center / virology
  • Immunoglobulin G / metabolism
  • Lymphocyte Activation
  • Lymphocytic Choriomeningitis / immunology
  • Lymphocytic Choriomeningitis / metabolism
  • Lymphocytic Choriomeningitis / virology
  • Lymphocytic choriomeningitis virus / immunology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Orthomyxoviridae / immunology*
  • Orthomyxoviridae Infections / immunology
  • Orthomyxoviridae Infections / metabolism
  • Orthomyxoviridae Infections / virology
  • Signal Transduction
  • T-Box Domain Proteins / physiology*
  • T-Lymphocytes, Helper-Inducer / cytology*
  • T-Lymphocytes, Helper-Inducer / immunology
  • T-Lymphocytes, Helper-Inducer / virology


  • Antibodies, Viral
  • Immunoglobulin G
  • T-Box Domain Proteins
  • T-box transcription factor TBX21