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

Patients with AIDS have fewer immune cells to defend against microbial invasion through the gut, a critical loss that may be caused by a tryptophan metabolite produced by other immune cells. Loss of the Defenders at the Gate Like archers stationed along the walls of a medieval castle, the immune system patrols the vulnerable parts of our body to keep pathogens at bay. One of these susceptible areas is the mucosa of the gastrointestinal tract, which is continually exposed to ingested and resident pathogens. This defense breaks down in patients with AIDS, in which sentinel immune cells [T helper 17 (TH17) cells] are missing from the gastrointestinal lining, potentially accounting for some secondary infections acquired by these patients. Favre and colleagues present evidence that the loss of these cells (and a parallel increase in immune suppressor cells) is caused by a metabolite of the amino acid tryptophan, new understanding that should help to prevent this serious consequence of HIV infection. HIV disease is in part an inflammatory disease, and activated T cells and cytokines circulate in patients’ blood, along with pathogen-derived molecules that trigger the innate immune system. The authors show that, in patients with serious AIDS, who are in this inflammatory state, the enzyme indoleamine 2,3-dioxygenase 1 (IDO1), which catabolizes tryptophan, is elevated in dendritic cells (DCs)—agents that present antigen to the immune system—from the blood, lymph nodes, and mucosa of the lower gastrointestinal tract. The inflammation-related molecules interferon γ and bacterial lipopolysaccharide can induce IDO1 in isolated DCs. This excess IDO1 activation increased blood concentrations of tryptophan catabolites in patients, and two of the catabolites increased the proportion of TH17 (activating) immune cells and decreased the proportion of T regulatory (Treg) (suppressing) immune cells in culture. In patients with serious disease, the authors found that the ratio of TH17 to Treg cells was much lower than normal, which hampers the ability of the body to raise an effective immune defense against pathogens. This dysfunctional system would set up a reinforcing loop that progressively depletes vulnerable tissues of their immune protection. Paradoxically, it seems, activation of the immune system by HIV may be contributing to the decline in immune function that is the hallmark of the disease. IDO1 inhibitors are being tested for their efficacy in interfering with this dangerous depletion of defenses. 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.