Human dendritic cells induce the differentiation of interleukin-21-producing T follicular helper-like cells through interleukin-12

Immunity. 2009 Jul 17;31(1):158-69. doi: 10.1016/j.immuni.2009.04.016.

Abstract

T follicular helper (Tfh) cells help development of antibody responses via interleukin-21 (IL-21). Here we show that activated human dendritic cells (DCs) induced naive CD4(+) T cells to become IL-21-producing Tfh-like cells through IL-12. CD4(+) T cells primed with IL-12 induced B cells to produce immunoglobulins in a fashion dependent on IL-21 and inducible costimulator (ICOS), thus sharing fundamental characteristics with Tfh cells. The induction of Tfh-like cells by activated DCs was inhibited by neutralizing IL-12. IL-12 induced two different IL-21-producers: IL-21(+)IFN-gamma(+)T-bet(+) Th1 cells and IL-21(+)IFN-gamma(-)T-bet(-) non-Th1 cells, in a manner dependent on signal transducer and activator of transcription 4 (STAT4). IL-12 also regulated IL-21 secretion by memory CD4(+) T cells. Thus, IL-12 produced by activated DCs regulates antibody responses via developing IL-21-producing Tfh-like cells and inducing IL-21 secretion from memory CD4(+) T cells. These data suggest that the developmental pathway of Tfh cells differs between mice and humans, which have considerable implications for vaccine development.

Publication types

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

MeSH terms

  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • Coculture Techniques
  • Cytokines / immunology
  • Cytokines / metabolism
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Humans
  • Interleukin-12 / immunology*
  • Interleukin-12 / metabolism
  • Interleukins / immunology*
  • Interleukins / metabolism
  • RNA, Small Interfering / immunology
  • RNA, Small Interfering / metabolism
  • STAT4 Transcription Factor / immunology*
  • STAT4 Transcription Factor / metabolism
  • T-Lymphocytes, Helper-Inducer / immunology*
  • T-Lymphocytes, Helper-Inducer / metabolism

Substances

  • Cytokines
  • Interleukins
  • RNA, Small Interfering
  • STAT4 Transcription Factor
  • STAT4 protein, human
  • Interleukin-12
  • interleukin-21

Grant support