Functional STAT3 deficiency compromises the generation of human T follicular helper cells

Blood. 2012 Apr 26;119(17):3997-4008. doi: 10.1182/blood-2011-11-392985. Epub 2012 Mar 8.


T follicular helper (Tfh) cells are critical for providing the necessary signals to induce differentiation of B cells into memory and Ab-secreting cells. Accordingly, it is important to identify the molecular requirements for Tfh cell development and function. We previously found that IL-12 mediates the differentiation of human CD4(+) T cells to the Tfh lineage, because IL-12 induces naive human CD4(+) T cells to acquire expression of IL-21, BCL6, ICOS, and CXCR5, which typify Tfh cells. We have now examined CD4(+) T cells from patients deficient in IL-12Rβ1, TYK2, STAT1, and STAT3 to further explore the pathways involved in human Tfh cell differentiation. Although STAT1 was dispensable, mutations in IL12RB1, TYK2, or STAT3 compromised IL-12-induced expression of IL-21 by human CD4(+) T cells. Defective expression of IL-21 by STAT3-deficient CD4(+) T cells resulted in diminished B-cell helper activity in vitro. Importantly, mutations in STAT3, but not IL12RB1 or TYK2, also reduced Tfh cell generation in vivo, evidenced by decreased circulating CD4(+)CXCR5(+) T cells. These results highlight the nonredundant role of STAT3 in human Tfh cell differentiation and suggest that defective Tfh cell development and/or function contributes to the humoral defects observed in STAT3-deficient patients.

Publication types

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

MeSH terms

  • Animals
  • B-Lymphocytes / cytology
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Differentiation*
  • Cells, Cultured
  • Cytokines / metabolism
  • Humans
  • Immunocompromised Host
  • Interleukin-12 / pharmacology*
  • Lymphocyte Activation
  • Mice
  • Mutation / genetics*
  • Receptors, Interleukin-12 / deficiency
  • Receptors, Interleukin-12 / genetics*
  • STAT1 Transcription Factor / genetics*
  • STAT1 Transcription Factor / metabolism
  • STAT3 Transcription Factor / deficiency
  • STAT3 Transcription Factor / genetics*
  • Signal Transduction
  • T-Lymphocytes, Helper-Inducer / cytology*
  • T-Lymphocytes, Helper-Inducer / immunology
  • T-Lymphocytes, Helper-Inducer / metabolism
  • TYK2 Kinase / genetics*
  • TYK2 Kinase / metabolism
  • Transcription Factors / metabolism


  • Cytokines
  • Receptors, Interleukin-12
  • STAT1 Transcription Factor
  • STAT3 Transcription Factor
  • Stat1 protein, mouse
  • Stat3 protein, mouse
  • Transcription Factors
  • Interleukin-12
  • TYK2 Kinase
  • Tyk2 protein, mouse