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

DH Munn, MD Sharma, B Baban, HP Harding, Y Zhang… - Immunity, 2005 - cell.com
DH Munn, MD Sharma, B Baban, HP Harding, Y Zhang, D Ron, AL Mellor
Immunity, 2005cell.com
Summary 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 …
Summary
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.
cell.com