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

By D. Munn, Madhav Sharma, B. Baban, H. Harding, Yuhong Zhang, D. Ron, A. Mellor. Immunity, 2005

1,238 citations recorded by the source corpus.

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.

Subfields: Biological Psychiatry, Cell Biology, Psychiatry and Mental health

View Paper: https://www.semanticscholar.org/paper/db4466d489ac9bf9d303eb94ce45970a88dc968f

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Biological Psychiatry

1. D. Munn
2. A. Mellor
3. Augusto Ochoa
4. P. Rodriguez
5. Erika L. Pearce
6. D. Pardoll
7. Jeffrey I. Gordon
8. W. Zou

In Cell Biology

1. A. Mellor
2. Craig B. Thompson
3. Jeffrey I. Gordon
4. D. Munn
5. Alec C. Kimmelman
6. M. Munder

In Psychiatry and Mental health

1. A. Mellor
2. D. Munn
3. D. Pardoll

Citations in the corpus

• Human nutrition, the gut microbiome, and immune system: envisioning the future (2011, background): “The presence of an intact amino-acid starvation response in T cells is essential for the immunosuppressive activity of tryptophan depletion by indoleamine-2,3-dioxygenas”
• The Combined Effects of Tryptophan Starvation and Tryptophan Catabolites Down-Regulate T Cell Receptor ζ-Chain and Induce a Regulatory Phenotype in Naive T Cells1 (2006, background): “These are not necessarily excluding possibilities and each might have a role in the biology of IDO (32).”
• Tryptophan catabolism in cancer: beyond IDO and tryptophan depletion. (2012, background): “T cells lacking GCN2 in mice are not susceptible to IDO-mediated anergy by myeloid cells, including dendritic cells in tumor-draining lymph nodes (19).”
• Targeting Metabolism to Improve the Tumor Microenvironment for Cancer Immunotherapy. (2020, background): “Increased IDO1 activity prevents the activation of effector T cells, inhibits NK cell function, supports Treg activation, and promotes the expansion and activation of DCs and MDSCs (Fallarino et al., 2003, 2006; Frumento et al., 2002; Munn et al., 2005).”
• Metabolic Interactions in the Tumor Microenvironment (2017, background): “First, local depletion of tryptophan by cancer cells and macrophages, through uptake and catabolism, suppresses antigen-specific T cell responses [79, 80] (Fig.”
• Arginase: an emerging key player in the mammalian immune system (2009, background): “Furthermore, various transcription factors (ATF-2, ATF-4, CHOP) are up-regulated and the mTOR-p70S6Kinase pathway is blunted in different mammalian cell types upon amino acid withdrawal (Rohde et al., 2001; Averous et al., 2004).”
• IDO in the Tumor Microenvironment: Inflammation, Counter-regulation and Tolerance (2016, neutral): “Then, via a process that is not yet well understood, GCN2 inhibits the activity of the mTORC2 complex, and prevents it from phosphorylating Akt on its activating Ser473 site [86].”
• Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. (2007, methodology): “In the case of CD8+ effector T cells, we have shown that activation of the GCN2 pathway leads to cell cycle arrest and anergy (9).”
• Kynurenines: Tryptophan’s metabolites in exercise, inflammation, and mental health (2017, background): “On the other hand, Trp starvationwill induce general control nonderepressible 2 (GCN2) kinase that inhibits G1 to S transition, inducing cell cycle arrest (99).”
• Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4 (2013, background): “…step in tryptophan degradation and the combination of local reduction in tryptophan levels and production of bioactive tryptophan metabolites (kynurenine) appear to exert suppressive activity on T cells (Munn et al., 1998, 2005; Fallarino et al., 2002; Frumento et al., 2002; Terness et al., 2002).”
• Arginine regulation by myeloid derived suppressor cells and tolerance in cancer: mechanisms and therapeutic perspectives (2008, background): “activates GCN2 kinase, which phosphorylates the translation initiation factor eIF2a (34).”
• Indoleamine 2,3-dioxygenase and tumor-induced tolerance. (2007, background): “Recently, the stress-responsive kinase general control nonderepressible 2 (GCN2) has been identified as a signaling molecule that enables T cells to sense and respond to stress conditions created by IDO (48, 49).”