Tryptophan catabolism by indoleamine 2,3-dioxygenase 1 alters the balance of TH17 to regulatory T cells in HIV disease.
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.
Favre
David
D
Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, CA 94110, USA.
Mold
Jeff
J
Hunt
Peter W
PW
Kanwar
Bittoo
B
Loke
P'ng
P
Seu
Lillian
L
Barbour
Jason D
JD
Lowe
Margaret M
MM
Jayawardene
Anura
A
Aweeka
Francesca
F
Huang
Yong
Y
Douek
Daniel C
DC
Brenchley
Jason M
JM
Martin
Jeffrey N
JN
Hecht
Frederick M
FM
Deeks
Steven G
SG
McCune
Joseph M
JM
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
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