title: Tryptophan catabolism by indoleamine 2,3-dioxygenase 1 alters the balance of TH17 to regulatory T cells in HIV disease.
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.
authors.affiliation: Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, CA 94110, USA.
authors.forename: David
authors.initials: D
authors.lastname: Favre
authors.forename: Jeff
authors.initials: J
authors.lastname: Mold
authors.forename: Peter W
authors.initials: PW
authors.lastname: Hunt
authors.forename: Bittoo
authors.initials: B
authors.lastname: Kanwar
authors.forename: P'ng
authors.initials: P
authors.lastname: Loke
authors.forename: Lillian
authors.initials: L
authors.lastname: Seu
authors.forename: Jason D
authors.initials: JD
authors.lastname: Barbour
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Lowe
authors.forename: Anura
authors.initials: A
authors.lastname: Jayawardene
authors.forename: Francesca
authors.initials: F
authors.lastname: Aweeka
authors.forename: Yong
authors.initials: Y
authors.lastname: Huang
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
authors.forename: Jason M
authors.initials: JM
authors.lastname: Brenchley
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Martin
authors.forename: Frederick M
authors.initials: FM
authors.lastname: Hecht
authors.forename: Steven G
authors.initials: SG
authors.lastname: Deeks
authors.forename: Joseph M
authors.initials: JM
authors.lastname: McCune
mesh_terms: D015095:3-Hydroxyanthranilic Acid / Q000378:metabolism; D001706:Biopsy; D018791:CD4 Lymphocyte Count; D016516:CD4-CD8 Ratio; D002478:Cells, Cultured; D012809:Colon, Sigmoid / Q000201:enzymology / Q000276:immunology / Q000821:virology; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology / Q000821:virology; D018450:Disease Progression; D015658:HIV Infections / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology* / Q000821:virology; D006679:HIV Seropositivity; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D007249:Inflammation / Q000201:enzymology / Q000276:immunology* / Q000821:virology; D018836:Inflammation Mediators / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology*; D007737:Kynurenine / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008198:Lymph Nodes / Q000201:enzymology / Q000276:immunology / Q000821:virology; D011446:Prospective Studies; D012007:Rectum / Q000201:enzymology / Q000276:immunology / Q000821:virology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D013997:Time Factors; D014364:Tryptophan / Q000378:metabolism*; D015854:Up-Regulation; D019562:Viral Load
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D018836:Inflammation Mediators; D020381:Interleukin-17; D008070:Lipopolysaccharides; D015095:3-Hydroxyanthranilic Acid; D007737:Kynurenine; D007371:Interferon-gamma; D014364:Tryptophan