Abstract
After activation, CD4(+) helper T (Th) cells differentiate into distinct effector subsets. Although chemokine (C-X-C motif) receptor 5-expressing T follicular helper (Tfh) cells are important in humoral immunity, their developmental regulation is unclear. Here we show that Tfh cells had a distinct gene expression profile and developed in vivo independently of the Th1 or Th2 cell lineages. Tfh cell generation was regulated by ICOS ligand (ICOSL) expressed on B cells and was dependent on interleukin-21 (IL-21), IL-6, and signal transducer and activator of transcription 3 (STAT3). However, unlike Th17 cells, differentiation of Tfh cells did not require transforming growth factor beta (TGF-beta) or Th17-specific orphan nuclear receptors RORalpha and RORgamma in vivo. Finally, naive T cells activated in vitro in the presence of IL-21 but not TGF-beta signaling preferentially acquired Tfh gene expression and promoted germinal-center reactions in vivo. This study thus demonstrates that Tfh is a distinct Th cell lineage.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adoptive Transfer
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Animals
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B-Lymphocytes / immunology
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Cell Differentiation / immunology*
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Cell Lineage / immunology*
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Flow Cytometry
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Gene Expression
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Gene Expression Profiling
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Germinal Center / cytology*
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Germinal Center / immunology
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Immunohistochemistry
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Inducible T-Cell Co-Stimulator Ligand
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Interleukin-17 / immunology
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Interleukin-17 / metabolism
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Interleukin-6 / immunology
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Interleukin-6 / metabolism
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Interleukins / immunology*
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Interleukins / metabolism
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Lymphocyte Activation / immunology
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Mice
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Mice, Mutant Strains
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Oligonucleotide Array Sequence Analysis
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Proteins / immunology
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Proteins / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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STAT3 Transcription Factor / immunology
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STAT3 Transcription Factor / metabolism
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Signal Transduction / immunology
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T-Lymphocyte Subsets / cytology*
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T-Lymphocyte Subsets / immunology
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T-Lymphocytes, Helper-Inducer / cytology*
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T-Lymphocytes, Helper-Inducer / immunology
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Transforming Growth Factor beta / immunology
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Transforming Growth Factor beta / metabolism
Substances
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Icosl protein, mouse
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Inducible T-Cell Co-Stimulator Ligand
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Interleukin-17
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Interleukin-6
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Interleukins
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Proteins
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STAT3 Transcription Factor
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Stat3 protein, mouse
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Transforming Growth Factor beta
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interleukin-21