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

644 Citations (Scopus)

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

Fingerprint

Indoleamine-Pyrrole 2,3,-Dioxygenase
Phosphotransferases
T-Lymphocytes
Dendritic Cells
Transfer RNA
Autoimmunity
Tryptophan
Neoplasms
Lymph Nodes
Transplants
Amino Acids

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. / Munn, David H.; Sharma, Madhav D.; Baban, Babak; Harding, Heather P.; Zhang, Yuhong; Ron, David; Mellor, Andrew L.

In: Immunity, Vol. 22, No. 5, 01.05.2005, p. 633-642.

Research output: Contribution to journalArticle

Munn, David H. ; Sharma, Madhav D. ; Baban, Babak ; Harding, Heather P. ; Zhang, Yuhong ; Ron, David ; Mellor, Andrew L. / GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. In: Immunity. 2005 ; Vol. 22, No. 5. pp. 633-642.
@article{7e4480680c534ae2b489e3ed6a738510,
title = "GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase",
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.",
author = "Munn, {David H.} and Sharma, {Madhav D.} and Babak Baban and Harding, {Heather P.} and Yuhong Zhang and David Ron and Mellor, {Andrew L.}",
year = "2005",
month = "5",
day = "1",
doi = "10.1016/j.immuni.2005.03.013",
language = "English (US)",
volume = "22",
pages = "633--642",
journal = "Immunity",
issn = "1074-7613",
publisher = "Cell Press",
number = "5",

}

TY - JOUR

T1 - GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase

AU - Munn, David H.

AU - Sharma, Madhav D.

AU - Baban, Babak

AU - Harding, Heather P.

AU - Zhang, Yuhong

AU - Ron, David

AU - Mellor, Andrew L.

PY - 2005/5/1

Y1 - 2005/5/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=19344377474&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=19344377474&partnerID=8YFLogxK

U2 - 10.1016/j.immuni.2005.03.013

DO - 10.1016/j.immuni.2005.03.013

M3 - Article

C2 - 15894280

AN - SCOPUS:19344377474

VL - 22

SP - 633

EP - 642

JO - Immunity

JF - Immunity

SN - 1074-7613

IS - 5

ER -