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: 15.84). 05/2010; 2(32):32ra36. DOI: 10.1126/scitranslmed.3000632
Source: PubMed


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.

Download full-text


Available from: Jason David Barbour
  • Source
    • "The gut mucosa of HIV-infected individuals exhibits a relative depletion of Th17 cells, a cell type that participates in containment of gut luminal bacteria and that supports barrier integrity via secretion of IL-17 and IL-22, cytokines which act on epithelial cells to promote production of antimicrobial peptides and mucins (Ouyang et al., 2008). Concomitant with Th17 cell depletion in HIV (which also occurs in non-human primate models using the closely related simian immunodeficiency virus [SIV]), has been observed a simultaneous upregulation of the immunomodulatory enzyme, indoleamine 2,3-dioxyge- nase 1(IDO1) (Favre et al., 2010). IDO1 is gene-induced primarily in macrophages and plasmacytoid dendritic cells by type I and II interferons, cytokines that are highly abundant in circulation during untreated HIV/SIV infection (Hosmalin and Lebon, 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Gut microbes can profoundly modulate mucosal barrier-promoting Th17 cells in mammals. A salient feature of HIV/simian immunodeficiency virus (SIV) immunopathogenesis is the loss of Th17 cells, which has been linked to increased activity of the immunomodulatory enzyme, indoleamine 2,3-dioxygenase 1 (IDO 1). The role of gut microbes in this system remains unknown, and the SIV-infected rhesus macaque provides a well-described model for HIV-associated Th17 loss and mucosal immune disruption. We observed a specific depletion of gut-resident Lactobacillus during acute and chronic SIV infection of rhesus macaques, which was also seen in early HIV-infected humans. This depletion in rhesus macaques correlated with increased IDO1 activity and Th17 loss. Macaques supplemented with a Lactobacillus-containing probiotic exhibited decreased IDO1 activity during chronic SIV infection. We propose that Lactobacillus species inhibit mammalian IDO1 and thus may help to preserve Th17 cells during pathogenic SIV infection, providing support for Lactobacillus species as modulators of mucosal immune homeostasis.
    Full-text · Article · Nov 2015 · Cell Reports
  • Source
    • "Another mechanism of IDO expression in APCs is mediated by regulatory T-cells (Treg) (39, 40). In HIV patients, an elevated enzymatic activity of IDO in APCs was associated with a reduced anti-viral T-cell response [reviewed elsewhere (41)], while depletion of Treg cells reconstituted anti-HIV immune responses (42). Similarly, in SIV-infected macaques, the expression of the Treg markers CTLA-4 and FoxP3 was increased in T-cells of mesenteric lymph nodes, spleen, and colon, organs with high viral load (43). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Initially, indoleamine-2,3-dioxygenase (IDO) has been introduced as a bactericidal effector mechanism and has been linked to T-cell immunosuppression and tolerance. In recent years, evidence has been accumulated that IDO also plays an important role during viral infections including HIV, influenza, and hepatitis B and C. Moreover, novel aspects about the role of IDO in bacterial infections and sepsis have been revealed. Here, we review these recent findings highlighting the central role of IDO and tryptophan metabolism in many major human infections. Moreover, we also shed light on issues concerning human-specific and mouse-specific host-pathogen interactions that need to be considered when studying the biology of IDO in the context of infections.
    Full-text · Article · Aug 2014 · Frontiers in Immunology
  • Source
    • "It appears that CD16-positive monocytes (5% of monocyte population [2]) are both more susceptible to infection and preferentially harbor the virus long-term [26]in vitro. We have also reported that immunoregulatory enzymes like HO-1 and indoleamine 2, 3-dioxygenase (IDO), may have beneficial effects in HIV-seropositive subjects [27]. While HO-1 expression in CD14+ monocytes was not predictive of CD4+ T cell recovery when measured at time points early after ART-mediated viral suppression, (Figure  4C) suppressive ART did restore homeostatic levels of HMOX1 gene expression (Figure  3B). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The level (or frequency) of circulating monocyte subpopulations such as classical (CD14(hi)CD16(-)) and non-classical (CD14(dim)CD16(+)) monocytes varies during the course of HIV disease progression and antiretroviral therapy (ART). We hypothesized that such variation and/or differences in the degree to which these cells expressed the immunoregulatory enzyme, heme oxygenase-1 (HO-1), would be associated with CD4(+) T cell recovery after the initiation of ART. This hypothesis was tested in a cross-sectional study of four groups of HIV-infected subjects, including those who were seronegative, untreated virologic controllers [detectable viral load (VL) of <1000 copies/mL], untreated virologic non-controllers [VL > 10,000 copies/mL], and ART-mediated virologic controllers [VL < 75 copies/mL]. A longitudinal analysis of ART-treated subjects was also performed along with regression analysis to determine which biomarkers were associated with and/or predictive of CD4(+) T cell recovery. Suppressive ART was associated with increased levels of classical monocyte subpopulations (CD14(hi)CD16(-)) and decreased levels of non-classical monocyte populations (CD14(dim)CD16(+)). Among peripheral blood mononuclear cells (PBMCs), HO-1 was found to be most highly up-regulated in CD14(+) monocytes after ex vivo stimulation. Neither the levels of monocyte subpopulations nor of HO-1 expression in CD14(+) monocytes were significantly associated with the degree of CD4(+) T cell recovery. Monocyte subpopulations and HO-1 gene expression were, however, restored to normal levels by suppressive ART. These results suggest that the level of circulating monocyte subpopulations and their expression of HO-1 have no evident relationship to CD4(+) T cell recovery after the initiation of ART.
    Full-text · Article · Aug 2014 · AIDS Research and Therapy
Show more