T cell apoptosis by tryptophan catabolism

Abstract

Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-catabolizing enzyme that, expressed by different cell types, has regulatory effects on T cells resulting from tryptophan depletion in specific local tissue microenvironments. Different mechanisms, however, might contribute to IDO-dependent immune regulation. We show here that tryptophan metabolites in the kynurenine pathway, such as 3-hydroxyanthranilic and quinolinic acids, will induce the selective apoptosis in vitro of murine thymocytes and of Th1 but not Th2 cells. T cell apoptosis was observed at relatively low concentrations of kynurenines, did not require Fas/Fas ligand interactions, and was associated with the activation of caspase-8 and the release of cytochrome c from mitochondria. When administered in vivo, the two kynurenines caused depletion of specific thymocyte subsets in a fashion qualitatively similar to dexamethasone. These data suggest that the selective deletion of T lymphocytes may be a major mechanism whereby tryptophan metabolism affects immunity under physiopathologic conditions.

Indoleamine 2,3 dioxygenase–mediated tryptophan catabolism regulates accumulation of Th1/Th17 cells in the joint in collagen‐induced arthritis

“…They also imply that IDO activity affects equally all T cells, regardless of their phenotype. Although there are no data on the susceptibility of Th17 cells to the action of IDO and tryptophan metabolites, there is evidence that both Th1 and Th2 cells are equally susceptible to IDO-mediated cell death (9,42). Alternatively, it is possible that IDO plays a role in blocking the generation of Th1 and Th17 cells.…”

Upregulation of tryptophanyl-tRNA synthethase adapts human cancer cells to nutritional stress caused by tryptophan degradation

“…Trp degradation is thought to suppress immune cells in two ways: Trp catabolites promote the differentiation of regulatory T cells (Treg) 6–8 and induce apoptosis of T cells 9 . On the other hand, Trp depletion has been implicated in the proliferation arrest of CD8 + T cells 10 by the accumulation of uncharged transfer RNA (tRNA) and subsequent activation of the general control non-derepressible-2 (GCN2) kinase pathway 11,12 , while Gcn2 in T cells has recently been shown to be dispensable for the suppression of antitumor immune responses in experimental melanomas 13 .…”

IDO expression in the brain: a double-edged sword

“…IDO expression is inducible by the proinflammatory cytokine interferon-γ (IFN-γ) and to a lower extent by interferon-β (IFN-β) in several cell types including macrophages, dendritic cells (DC), and fibroblasts [2][3][4][5]. In the brain, murine and human microglia have been shown to express IDO upon treatment with IFN-γ [6,7].…”