GCN2 Kinase in T Cells Mediates Proliferative Arrest and Anergy Induction in Response to Indoleamine 2,3-Dioxygenase
Copyright policy )GCN2 Kinase in T Cells Mediates Proliferative Arrest and Anergy Induction in Response to Indoleamine 2,3-Dioxygenase
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.
- New York University United States
- Georgia Regents University United States
T-Lymphocytes, Immunology, Mice, Transgenic, In Vitro Techniques, Protein Serine-Threonine Kinases, Mice, Immunology and Allergy, Animals, Indoleamine-Pyrrole 2,3,-Dioxygenase, Cell Proliferation, Clonal Anergy, Mice, Knockout, Dendritic Cells, Adoptive Transfer, Enzyme Activation, Mice, Inbred C57BL, Infectious Diseases, CCAAT-Enhancer-Binding Proteins, Lymphocyte Culture Test, Mixed, Protein Kinases, Transcription Factor CHOP, Signal Transduction, Transcription Factors
T-Lymphocytes, Immunology, Mice, Transgenic, In Vitro Techniques, Protein Serine-Threonine Kinases, Mice, Immunology and Allergy, Animals, Indoleamine-Pyrrole 2,3,-Dioxygenase, Cell Proliferation, Clonal Anergy, Mice, Knockout, Dendritic Cells, Adoptive Transfer, Enzyme Activation, Mice, Inbred C57BL, Infectious Diseases, CCAAT-Enhancer-Binding Proteins, Lymphocyte Culture Test, Mixed, Protein Kinases, Transcription Factor CHOP, Signal Transduction, Transcription Factors
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