The transforming growth factor beta signaling pathway is critical for the formation of CD4 T follicular helper cells and isotype-switched antibody responses in the lung mucosa

Elife. 2015 Jan 8;4:e04851. doi: 10.7554/eLife.04851.


T follicular helper cells (Tfh) are crucial for the initiation and maintenance of germinal center (GC) reactions and high affinity, isotype-switched antibody responses. In this study, we demonstrate that direct TGF-β signaling to CD4 T cells is important for the formation of influenza-specific Tfh cells, GC reactions, and development of isotype-switched, flu-specific antibody responses. Early during infection, TGF-β signaling suppressed the expression of the high affinity IL-2 receptor α chain (CD25) on virus-specific CD4 T cells, which tempered IL-2 signaling and STAT5 and mammalian target of rapamycin (mTOR) activation in Tfh precursor CD4 T cells. Inhibition of mTOR allowed for the differentiation of Tfh cells in the absence of TGF-βR signaling, suggesting that TGF-β insulates Tfh progenitor cells from IL-2-delivered mTOR signals, thereby promoting Tfh differentiation during acute viral infection. These findings identify a new pathway critical for the generation of Tfh cells and humoral responses during respiratory viral infections.

Keywords: T follicular helper cells; TGF-beta; antibody; cytokines; immunology; mouse; viral infection.

Publication types

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

MeSH terms

  • Animals
  • Antibody Formation / immunology*
  • B-Lymphocytes / immunology
  • Cell Differentiation / immunology
  • Gene Expression Profiling
  • Germinal Center / immunology
  • Immunoglobulin Class Switching / immunology*
  • Lung / immunology*
  • Lung / pathology
  • Lung / virology
  • Mice
  • Mucous Membrane / immunology*
  • Mucous Membrane / pathology
  • Mucous Membrane / virology
  • Orthomyxoviridae / physiology
  • Orthomyxoviridae Infections / immunology
  • Orthomyxoviridae Infections / pathology
  • Signal Transduction*
  • Species Specificity
  • T-Lymphocytes, Helper-Inducer / immunology*
  • TOR Serine-Threonine Kinases / metabolism
  • Transforming Growth Factor beta / metabolism*


  • Transforming Growth Factor beta
  • TOR Serine-Threonine Kinases