HIV inhibits CD4+ T-cell proliferation by inducing indoleamine 2,3-dioxygenase in plasmacytoid dendritic cells

Abstract

IntroductionThe immunologic hallmark of the acquired immunodeficiency syndrome (AIDS), resulting from infection with the human immunodeficiency virus type-1 (HIV), is the depletion of CD4 ϩ T cells. 1 However, qualitative alterations of the function of circulating T cells are observed that do not appear to be related to the decline of CD4 ϩ T-cell number. [2][3][4][5] In vitro T-cell responses are impaired in peripheral blood mononuclear cells (PBMCs) from HIV-infected patients. Thus, proliferative responses to HIV epitopes are lost early during infection, 6-8 followed by sequential impairment of T-helper cell responses to recall antigens and mitogens. 9 This progressive loss of T-cell function during the course of HIV disease is predictive for the time of onset of AIDS and death. 10 Tryptophan (Trp) catabolism mediated by indoleamine 2,3-dioxygenase (IDO) is an immunoregulatory mechanism that limits T-cell proliferation by depletion of the essential amino acid Trp and/or accumulation of catabolites with immune-suppressive activity (kynurenines, kyn). 11 Alterations of this mechanism have been suggested to be involved in (1) development of autoimmune conditions, such as multiple sclerosis and autoimmune diabetes 12,13 ; (2) failure of immune surveillance of tumor cells 14 ; and (3) rejection of semiallogenic fetuses. 15,16 The molecular basis for T-cell hyporesponsiveness in IDO-mediated Trp depletion has been recently clarified. The consequence of reduction in available Trp in the extracellular microenvironment is the accumulation of uncharged Trp-specific transfer RNA (free-tRNA trp ) in the cytoplasm. 17 Free-tRNA trp binds to the GCN2 kinase, a key enzyme of the cellular stress-response system. 17 Once activated by ligation to free-tRNA trp , the GCN2 kinase initiates a cascade of events leading to arrest of the cell cycle, which is, in turn, the ultimate effect of tryptophan starvation. 17 Increased IDO-mediated tryptophan catabolism during HIV infection has been reported. [18][19][20][21] IDO is induced in macrophages by HIV infection, and has been suggested to be involved in the induction of HIV encephalitis and AIDS-related dementia. 20,22,23 Inhibition of HIV-induced IDO in brain macrophages enhanced HIV-specific cytotoxic T-lymphocyte (CTL) response and elimination of infected macrophages in a murine model. 24 We recently reported that IDO mRNA expression is increased in the tonsils of HIV-infected patients in whom viral replication is not controlled by effective antiretroviral therapy (ART). 25 A similar increase of IDO was found in lymphoid tissues of macaques during acute simian immunodeficiency virus (SIV) and chronic SIV/HIV infection, and correlated with reduced immune responses. 26,27 However, the functional role of IDO in HIV-associated immunosuppression is unknown.In the present study, we tested the effect of 1-methyl-tryptophan (1-mT), a competitive inhibitor of IDO, on the stimulation of The online version of this article contains a data supplement.The publication costs of this article were ...

Distinctive TLR7 Signaling, Type I IFN Production, and Attenuated Innate and Adaptive Immune Responses to Yellow Fever Virus in a Primate Reservoir Host

“…Induction of immunosuppressive mediators could, as has been hypothesized following SIV infection (19), also play a role in the active inhibition of damaging immune responses to YFV in SMs, for instance, by induction of IDO following exposure to HIV and other TLR7 and TLR9 agonists (63), an NF-kB-mediated response that we have found to be preserved in SMs (data not shown). In light of evidence indicating that potentially immunosuppressive mediators, such as IDO, are produced by pDCs in response to activation of the TLR7 signaling pathway, it is tempting to speculate that such mediators might contribute to the transient diminution of SIV viremia we observed in SMs following vaccination with YF-17D (but not the non-TLR7/9-active virus, MVA) (64,65). Conceivably, both the limited CD4 + T cell activation and induction of immunosuppressive pathways might be involved in protecting natural hosts from disease.…”

Antiviral Vaccines License T Cell Responses by Suppressing Granzyme B Levels in Human Plasmacytoid Dendritic Cells

“…In contrast, pDC appear to hold an important position in the fine-tuning and modulation of T cell responses including those T cell responses that are initiated by other types of APC (3,32,35). As we and others have shown, pDC are able to express and secrete a series of molecules with immunomodulatory effects on T cells including IDO (36), ICOS ligand (37), and GrB (6). GrB takes an exceptional position in this context because it was shown to be necessary for the function of regulatory T cells (22,38) and to be expressed by other regulatory cell subsets such as human regulatory B cells (39).…”

Activation of the noncanonical NF-κB pathway by HIV controls a dendritic cell immunoregulatory phenotype

“…In human pDC, it appears that PI3K-p38 MAPK mediated phosphorylation of STAT1 can occur independently of type I interferons after TLR stimulation (43,44). Therefore, based on our data and others' (15) we speculate that direct TLR activation of STAT1 may bypass the requirement for IFN signaling, and p52/ RelB may act in synergy with or facilitate STAT1 binding to IFNstimulated response element or IFN-γ-activated sequence elements for IDO induction (Fig. S6).…”