Transcriptional mechanisms underlying lymphocyte tolerance

Cell. 2002 Jun 14;109(6):719-31. doi: 10.1016/s0092-8674(02)00767-5.


In lymphocytes, integration of Ca2+ and other signaling pathways results in productive activation, while unopposed Ca2+ signaling leads to tolerance or anergy. We show that the Ca2+-regulated transcription factor NFAT has an integral role in both aspects of lymphocyte function. Ca2+/calcineurin signaling induces a limited set of anergy-associated genes, distinct from genes induced in the productive immune response; these genes are upregulated in vivo in tolerant T cells and are largely NFAT dependent. T cells lacking NFAT1 are resistant to anergy induction; conversely, NFAT1 induces T cell anergy if prevented from interacting with its transcriptional partner AP-1 (Fos/Jun). Thus, in the absence of AP-1, NFAT imposes a genetic program of lymphocyte anergy that counters the program of productive activation mediated by the cooperative NFAT:AP-1 complex.

Publication types

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

MeSH terms

  • Animals
  • CD28 Antigens / biosynthesis
  • Calcineurin / metabolism
  • Calcium / metabolism
  • Cell Death
  • Cell Division
  • Chelating Agents / pharmacology
  • Clonal Anergy
  • Cytokines / metabolism
  • DNA-Binding Proteins / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme-Linked Immunosorbent Assay
  • Immunoblotting
  • Ionomycin / pharmacology
  • Lymphocytes / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Models, Biological
  • NFATC Transcription Factors
  • Nuclear Proteins*
  • Retroviridae / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • T-Lymphocytes / metabolism
  • Th1 Cells / metabolism
  • Time Factors
  • Transcription Factor AP-1 / metabolism
  • Transcription Factors / metabolism
  • Transcription, Genetic*
  • Up-Regulation


  • CD28 Antigens
  • Chelating Agents
  • Cytokines
  • DNA-Binding Proteins
  • NFATC Transcription Factors
  • Nuclear Proteins
  • Transcription Factor AP-1
  • Transcription Factors
  • Ionomycin
  • Calcineurin
  • Calcium