GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase

David H. Munn, Madhav D. Sharma, Babak Baban, Heather P. Harding, Yuhong Zhang, David Ron, Andrew L. Mellor

Research output: Contribution to journalArticle

687 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)633-642
Number of pages10
JournalImmunity
Volume22
Issue number5
DOIs
StatePublished - May 1 2005

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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