Article

Tryptophan Catabolism by Indoleamine 2,3-Dioxygenase 1 Alters the Balance of TH17 to Regulatory T Cells in HIV Disease

Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, CA 94110, USA.
Science translational medicine (Impact Factor: 14.41). 05/2010; 2(32):32ra36. DOI: 10.1126/scitranslmed.3000632
Source: PubMed

ABSTRACT The pathogenesis of human and simian immunodeficiency viruses is characterized by CD4(+) T cell depletion and chronic T cell activation, leading ultimately to AIDS. CD4(+) T helper (T(H)) cells provide protective immunity and immune regulation through different immune cell functional subsets, including T(H)1, T(H)2, T regulatory (T(reg)), and interleukin-17 (IL-17)-secreting T(H)17 cells. Because IL-17 can enhance host defenses against microbial agents, thus maintaining the integrity of the mucosal barrier, loss of T(H)17 cells may foster microbial translocation and sustained inflammation. Here, we study HIV-seropositive subjects and find that progressive disease is associated with the loss of T(H)17 cells and a reciprocal increase in the fraction of the immunosuppressive T(reg) cells both in peripheral blood and in rectosigmoid biopsies. The loss of T(H)17/T(reg) balance is associated with induction of indoleamine 2,3-dioxygenase 1 (IDO1) by myeloid antigen-presenting dendritic cells and with increased plasma concentration of microbial products. In vitro, the loss of T(H)17/T(reg) balance is mediated directly by the proximal tryptophan catabolite from IDO metabolism, 3-hydroxyanthranilic acid. We postulate that induction of IDO may represent a critical initiating event that results in inversion of the T(H)17/T(reg) balance and in the consequent maintenance of a chronic inflammatory state in progressive HIV disease.

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    • "Recently, the role of its enzymatic products, kynurenines, has also been characterized. Kynurenines are potent negative regulators of inflammation and T cell activity (Munn et al., 2005; Zelante et al., 2009; Favre et al., 2010; Medzhitov et al., 2011). So while the role of IDO on intracellular tryptophan is clear, its pleiotropic effects in pathogen defence have been more difficult to pin down (Blumenthal et al., 2012). "
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