GCN2 Kinase in T Cells Mediates Proliferative Arrest and Anergy Induction in Response to Indoleamine 2,3-dioxygenase

Immunity. 2005 May;22(5):633-42. doi: 10.1016/j.immuni.2005.03.013.

Abstract

Indoleamine 2,3 dioxygenase (IDO) catabolizes the amino acid tryptophan. IDO-expressing immunoregulatory dendritic cells (DCs) have been implicated in settings including tumors, autoimmunity, and transplant tolerance. However, the downstream molecular mechanisms by which IDO functions to regulate T cell responses remain unknown. We now show that IDO-expressing plasmacytoid DCs activate the GCN2 kinase pathway in responding T cells. GCN2 is a stress-response kinase that is activated by elevations in uncharged tRNA. T cells with a targeted disruption of GCN2 were not susceptible to IDO-mediated suppression of proliferation in vitro. In vivo, proliferation of GCN2-knockout T cells was not inhibited by IDO-expressing DCs from tumor-draining lymph nodes. IDO induced profound anergy in responding wild-type T cells, but GCN2-knockout cells were refractory to IDO-induced anergy. We hypothesize that GCN2 acts as a molecular sensor in T cells, allowing them to detect and respond to conditions created by IDO.

Publication types

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

MeSH terms

  • Adoptive Transfer
  • Animals
  • CCAAT-Enhancer-Binding Proteins / genetics
  • CCAAT-Enhancer-Binding Proteins / metabolism
  • Cell Proliferation
  • Clonal Anergy
  • Dendritic Cells / immunology
  • Enzyme Activation
  • In Vitro Techniques
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Lymphocyte Culture Test, Mixed
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Protein Kinases / deficiency
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Protein-Serine-Threonine Kinases
  • Signal Transduction
  • T-Lymphocytes / cytology*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / enzymology*
  • T-Lymphocytes / immunology
  • Transcription Factor CHOP
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tryptophan / pharmacology
  • Tryptophan Oxygenase / genetics
  • Tryptophan Oxygenase / metabolism*

Substances

  • CCAAT-Enhancer-Binding Proteins
  • Ddit3 protein, mouse
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Transcription Factors
  • Transcription Factor CHOP
  • Tryptophan
  • Tryptophan Oxygenase
  • Protein Kinases
  • Eif2ak4 protein, mouse
  • Protein-Serine-Threonine Kinases