Role of T-bet in commitment of TH1 cells before IL-12-dependent selection

Science. 2001 Jun 8;292(5523):1907-10. doi: 10.1126/science.1059835.

Abstract

How cytokines control differentiation of helper T (TH) cells is controversial. We show that T-bet, without apparent assistance from interleukin 12 (IL-12)/STAT4, specifies TH1 effector fate by targeting chromatin remodeling to individual interferon-gamma (IFN-gamma) alleles and by inducing IL-12 receptor beta2 expression. Subsequently, it appears that IL-12/STAT4 serves two essential functions in the development of TH1 cells: as growth signal, inducing survival and cell division; and as trans-activator, prolonging IFN-gamma synthesis through a genetic interaction with the coactivator, CREB-binding protein. These results suggest that a cytokine does not simply induce TH fate choice but instead may act as an essential secondary stimulus that mediates selective survival of a lineage.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alleles
  • Animals
  • CREB-Binding Protein
  • Cell Differentiation
  • Cell Division
  • Cell Lineage
  • Cells, Cultured
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation
  • Histones / metabolism
  • Interferon-gamma / biosynthesis*
  • Interferon-gamma / genetics
  • Interleukin-12 / metabolism*
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Nuclear Proteins / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Interleukin / metabolism
  • Receptors, Interleukin-12
  • STAT4 Transcription Factor
  • Signal Transduction
  • T-Box Domain Proteins
  • Th1 Cells / cytology
  • Th1 Cells / immunology*
  • Th1 Cells / metabolism
  • Trans-Activators / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • DNA-Binding Proteins
  • Histones
  • Il12rb2 protein, mouse
  • Nuclear Proteins
  • RNA, Messenger
  • Receptors, Interleukin
  • Receptors, Interleukin-12
  • STAT4 Transcription Factor
  • Stat4 protein, mouse
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Trans-Activators
  • Transcription Factors
  • Interleukin-12
  • Interferon-gamma
  • CREB-Binding Protein
  • Crebbp protein, mouse