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New Aging/HIV Study-blocking inflammation: Tryptophan Catabolism by Indoleamine 2,3-Dioxygenase 1 Alters the Balance of TH17 to Regulatory T Cells in HIV Disease
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Sci Transl Med 19 May 2010:
Vol. 2, Issue 32, p. 32ra36
"IDO1-dependent tryptophan catabolism may be an important link between immune activation and the gradual decline of immune function seen in progressive HIV infection. Blockade of IDO1 with a pharmacological inhibitor (for example, 1-methy-d-tryptophan) in combination with antiretroviral therapy has shown some promise in lowering the viral load in pathogenic SIV infection (58) and enhancing the elimination of virus-infected macrophages in a murine model of HIV encephalitis (59). Clinical trials are currently under way to assess the efficacy of IDO1 inhibitors for cancer immunotherapy, and small-molecule inhibitors are being developed that may prove useful in a variety of clinical settings. Future efforts to determine whether blockade of IDO1 can alter the balance of T cell subsets in disease states represent an important goal for understanding HIV pathogenesis as well as other diseases characterized by chronic inflammation."
David Favre1,*, Jeff Mold1,*, Peter W. Hunt2, Bittoo Kanwar1,3, P'ng Loke1,, Lillian Seu1, Jason D. Barbour2, Margaret M. Lowe1, Anura Jayawardene4, Francesca Aweeka4, Yong Huang5, Daniel C. Douek6, Jason M. Brenchley7, Jeffrey N. Martin8, Frederick M. Hecht2, Steven G. Deeks2 and Joseph M. McCune1,
1Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, CA 94110, USA.
2HIV/AIDS Program, Department of Medicine, University of California, San Francisco, CA 94110, USA.
3Division of Gastroenterology, Department of Pediatrics, University of California, San Francisco, CA 94110, USA.
4Drug Research Unit, Department of Clinical Pharmacy, University of California, San Francisco, CA 94143, USA.
5Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94143, USA.
6Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
7Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
8Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94143, USA.
To whom correspondence should be addressed. E-mail: mike.mccune@ucsf.edu
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 (TH) cells provide protective immunity and immune regulation through different immune cell functional subsets, including TH1, TH2, T regulatory (Treg), and interleukin-17 (IL-17)-secreting TH17 cells. Because IL-17 can enhance host defenses against microbial agents, thus maintaining the integrity of the mucosal barrier, loss of TH17 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 TH17 cells and a reciprocal increase in the fraction of the immunosuppressive Treg cells both in peripheral blood and in rectosigmoid biopsies. The loss of TH17/Treg 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 TH17/Treg 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 TH17/Treg balance and in the consequent maintenance of a chronic inflammatory state in progressive HIV disease.
Introduction
Accumulating evidence suggests that the pathology associated with HIV infection may result from persistent and uncontrolled inflammation (1). This hypothesis is supported by the observations that chronic, untreated HIV infection is associated with systemic immune activation, including increases in nonspecific T cell activation and proliferation (2), elevated inflammatory cytokines and chemokines (3), and increased concentration of catabolic by-products such as neopterin and kynurenine in the circulation (4). The central role of T cell activation and inflammation in HIV disease pathogenesis is supported by the consistent observation that activated (CD8+CD38+HLA-DR+) circulating T cells predict disease progression independent of viral load (5). Other markers of inflammation [including interleukin-6 (IL-6) and high-sensitivity reactive protein] are also independent predictors of disease progression in both treated and untreated HIV infection (6).
Indoleamine 2,3-dioxygenase 1 (IDO1; previously referred as IDO or INDO) is the main inducible and rate-limiting enzyme for the catabolism of the amino acid tryptophan through the kynurenine pathway (7) (although there may be a separate and perhaps overlapping role for the newly discovered enzyme, IDO2) (8). Predominantly found in macrophages and dendritic cells (DCs), IDO1 is up-regulated by interferons (IFNs) and by agonists of Toll-like receptors (TLRs) (7). Increased catabolism of tryptophan by IDO1 suppresses T cell responses in a variety of diseases or states, including autoimmune disorders (9), allograft rejection (10), viral infections (11), cancer (12), and pregnancy (13). Such suppression is thought to occur either because IDO1 depletes the essential amino acid tryptophan or because it produces tryptophan catabolites that are toxic to T cells (or both) (14, 15). In either case, the ability of IDO1 to suppress immune responses has raised the possibility that it may contribute to the immunodeficiency seen in individuals with progressive HIV disease (4).
Although CD4+ T cell depletion is pathognomonic for HIV disease progression, the specific subsets of CD4+ T helper (TH) cells that are affected remain elusive. Four main lineages of CD4+ TH cells have been characterized, including IFN-γ-secreting TH1 cells, IL-4-secreting TH2 cells, FoxP3-expressing T regulatory (Treg) cells, and IL-17-secreting TH17 cells. These lineages derive from naïve CD4+ T cells under polarizing and mutually exclusive conditions in vitro, and presumably in vivo (16), and provide protective immunity against intracellular (TH1) or extracellular pathogens (TH2) as well as immune regulation and tolerance (Treg) or protection against bacterial infection at mucosal sites (TH17) (17). We recently reported that simian immunodeficiency virus (SIV) infection leading to AIDS in macaques was associated with a change in the balance of Treg and TH17 cells, whereas this balance was maintained in natural SIV infections that do not lead to AIDS in African green monkeys (18). TH17 cells are also lost in HIV infection, which has been suggested to account for a breakdown in mucosal immunity and an increase in microbial translocation across the gastrointestinal mucosa (19). Despite the selective depletion of TH17 cells during pathogenic SIV and HIV infection, there is no evidence that these cells are preferentially infected, and instead, bystander cell death may account for their loss (19). Studies in mice have suggested that IDO1 regulates the balance of TH17 to Treg cells, but the mechanism of such regulation remains unknown (20, 21). We hypothesized that elevated IDO1 activity may alter the balance of TH17 to Treg cells after infection by HIV, thereby establishing a positive feedback loop that increases systemic immune activation and accelerates disease progression. Here, we extend previous studies to show that enhanced IDO1 activity is associated with HIV disease progression and demonstrate that such activity results in an imbalance of TH17 and Treg cells in the peripheral blood and in rectosigmoid tissue that is both linked to HIV disease progression and mediated by the tryptophan catabolite 3-hydroxyanthranilic acid (3-HAA).
Discussion
Research on aberrant immune system features in host-pathogen interactions, on inflammatory syndromes and autoimmune diseases, and on primary immune deficiencies has highlighted the importance of two immune cell lineages derived from a common progenitor under reciprocal and mutually exclusive differentiation pathways (35-38): TH17 cells, which produce the proinflammatory cytokine IL-17, and FoxP3+ Treg cells, whose function is immunosuppressive (42-45). TH17 cells, in particular, have been causally related both to chronic inflammatory diseases (46) and to host defenses against microbial agents (47). An intriguing developmental link also exists between the activity of the enzyme IDO1 and the differentiation of TH17 and Treg cells from naïve T cells. The products of IDO1, tryptophan catabolites such as kynurenines, can induce FoxP3 expression and the generation of Treg cells and can blunt the generation of TH17 cells and the expression of the master regulator of TH17 differentiation, the RORc gene transcription factor (retinoic acid receptor-related orphan receptor-γt) (20, 21, 48). Similarly, IDO1-mediated tryptophan deprivation and the amino acid starvation response can induce Treg development and blunt TH17 conversion (49, 50). Because IDO1 metabolism is related both to this Treg to TH17 developmental switch and to HIV pathogenesis (4), we explored the relations between HIV disease, TH17 and Treg cell populations, and IDO1 metabolism. We have demonstrated here that the balance between TH17 and Treg cells in blood and in the rectosigmoid mucosa is altered during HIV disease progression toward a lower proportion of TH17 cells and an increased proportion of Treg cells and that this change is directly associated with IDO1 activity. We also demonstrate that 3-HAA, a proximal catabolite of tryptophan catabolism, is capable of tipping the TH17/Treg balance toward the immunosuppressive Treg pathway in vitro.
The deleterious nature of chronic inflammation has long been recognized in situations where the immune system fails to effectively clear pathogenic organisms (51). Certain strains of lymphocytic choriomeningitis virus (LCMV), for instance, can establish a chronic infection that eventually results in exhaustion of the immune system (51). More than 50 years ago, however, it was noted that vertical transmission of LCMV from mother to child results in chronic infection in the absence of overt pathology (52), a result of a failure of the immune system to attack LCMV (52, 53). A similar situation occurs in nonpathogenic SIV infection in most African nonhuman primates (54). These animals maintain high viral loads in the absence of disease progression with reduced inflammatory responses during the chronic phase of the infection (18, 54). Thus, disease associated with chronic infections such as HIV may not be so much a result of the virus attacking the host but rather may be a result of the host's immune system attacking the virus. In this regard, IDO1 may be one of many mediators through which an activated immune system and inflammation lead to a loss of T cell function and, ultimately, immunosuppression.
We propose here the existence of a feedback loop that leads to elevated systemic immune activation during pathogenic HIV infection (44). We hypothesize that systemic inflammation in the acute stage of HIV infection, combined with the early loss of immune function caused by TH17 cell depletion in the gastrointestinal tract, results in elevated IDO1 activity throughout the chronic phase of HIV infection. Such elevated activity, in turn, leads to the generation of catabolites (3-HAA) that alter T cell differentiation pathways in a manner that leads to further immunosuppression. Previous reports indicate that acute HIV and SIV infections result in a massive increase in IFN concentrations in part through direct activation of pDCs by HIV virions (24, 25). Activated pDCs are then prompted to up-regulate IDO1 through autocrine IFN signaling and TLR stimulation by HIV components (for example, ssRNA or CpG) (26). The early burst of IDO1 activity results in a transient alteration in the T cell response favoring the up-regulation of FoxP3 and generation of Treg cells over the differentiation of TH17 cells. In nonpathogenic SIV infection, the IFN response is eventually curtailed and IDO1 activity returns to baseline levels (18). However, in pathogenic SIV infection and chronic HIV infection, IFN remains high, leading to the persistence of elevated IDO1 activity, likely from both pDCs and, on the basis of our data here, mDCs as well (18, 25). This chronic activation of the IDO1 pathway diminishes the host's capacity to generate TH17 cells and favors the generation of Treg cells. The net outcome is a progressive loss of the mucosal immune barrier and increased susceptibility to mucosal infections, a result of fewer TH17 cells, augmented by more Treg cells, which dampens T cell immunity to HIV and other pathogenic organisms (44).
Although we have demonstrated that 3-HAA can specifically invert the ratio of TH17 and Treg cells, we have yet to determine the mechanism by which this occurs. Previous studies have shown that 3-HAA blocks T cell activation and promotes T cell death (15, 41). These studies generally used higher concentrations of 3-HAA than reported here (and we have also observed cellular toxicity at concentrations >100 mM). 3-HAA has also been found to inhibit TH1 and TH2 responses in a variety of in vivo settings, including allergy (55), organ transplantation (10), experimental autoimmune encephalomyelitis (9), and colitis (56). One study has shown that 3-HAA mediates its inhibitory effects on T cell activation and proliferation by directly inhibiting the phosphorylation of phosphoinositide-dependent kinase 1 and by preventing nuclear factor κB activation after T cell receptor stimulation (57). However, we did not observe increases in T cell death or inhibition of proliferation at lower concentrations of 3-HAA (25 to 100 mM) despite alterations in TH17 and Treg cell differentiation.
IDO1-dependent tryptophan catabolism may be an important link between immune activation and the gradual decline of immune function seen in progressive HIV infection. Blockade of IDO1 with a pharmacological inhibitor (for example, 1-methy-d-tryptophan) in combination with antiretroviral therapy has shown some promise in lowering the viral load in pathogenic SIV infection (58) and enhancing the elimination of virus-infected macrophages in a murine model of HIV encephalitis (59). Clinical trials are currently under way to assess the efficacy of IDO1 inhibitors for cancer immunotherapy, and small-molecule inhibitors are being developed that may prove useful in a variety of clinical settings. Future efforts to determine whether blockade of IDO1 can alter the balance of T cell subsets in disease states represent an important goal for understanding HIV pathogenesis as well as other diseases characterized by chronic inflammation.
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