Sharma MD, Baban B, Chandler P, Hou DY, Singh N, Yagita H et al.. Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. J Clin Invest 117: 2570-2582

Department of Pediatrics, School of Medicine, Medical College of Georgia, Augusta, Georgia 30912, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 10/2007; 117(9):2570-82. DOI: 10.1172/JCI31911
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A small population of plasmacytoid DCs (pDCs) in mouse tumor-draining LNs can express the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO). We show that these IDO+ pDCs directly activate resting CD4+CD25+Foxp3+ Tregs for potent suppressor activity. In vivo, Tregs isolated from tumor-draining LNs were constitutively activated and suppressed antigen-specific T cells immediately ex vivo. In vitro, IDO+ pDCs from tumor-draining LNs rapidly activated resting Tregs from non-tumor-bearing hosts without the need for mitogen or exogenous anti-CD3 crosslinking. Treg activation by IDO+ pDCs was MHC restricted, required an intact amino acid-responsive GCN2 pathway in the Tregs, and was prevented by CTLA4 blockade. Tregs activated by IDO markedly upregulated programmed cell death 1 ligand 1 (PD-L1) and PD-L2 expression on target DCs, and the ability of Tregs to suppress target T cell proliferation was abrogated by antibodies against the programmed cell death 1/PD-L (PD-1/PD-L) pathway. In contrast, Tregs activated by anti-CD3 crosslinking did not cause upregulation of PD-Ls, and suppression by these cells was unaffected by blocking the PD-1/PD-L pathway. Tregs isolated from tumor-draining LNs in vivo showed potent PD-1/PD-L-mediated suppression, which was selectively lost when tumors were grown in IDO-deficient hosts. We hypothesize that IDO+ pDCs create a profoundly suppressive microenvironment within tumor-draining LNs via constitutive activation of Tregs.

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Available from: Andrew L Mellor, Oct 06, 2015
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    • "Liu et al. correlated reduced IDO levels to reduced Foxp3 expression in placentae from preeclamptic women and suggested that loss of fetal tolerance in preeclampsia is due to reduced T regulatory cells, however, upon preliminary analysis we observed no significant difference in Foxp3 expression via qPCR in IDO-KO versus control placentae (IDO-KO n = 5: 22.5 AE 0.39, vs. control n = 6: 24.3 AE 1.2, P = 0.2201; Liu et al. 2011). These data suggest that the Treg compartment is likely to be intact, however, future studies will examine the possibility of decreased Treg function (suppressive activity) versus reduced Treg numbers in IDO-KO mice (Sharma et al. 2007; Baban et al. 2009). Finally, depleting T cells of tryptophan inhibits their expansion due to an arrest in the cell cycle at the G1 phase, providing some hints at the molecular mechanisms through which IDO could contribute to T-cell function (Taylor et al. 1996; Munn et al. 1999; Kudo et al. 2003). "
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    ABSTRACT: Preeclampsia is a cardiovascular disorder of late pregnancy that is, commonly characterized by hypertension, renal structural damage and dysfunction, and fetal growth restriction. Prevailing etiologic models of this disorder include T-cell dysfunction as an initiating cause of preeclampsia. Indoleamine 2,3-dioxygenase (IDO), an enzyme that mediates the conversion of tryptophan to kynurenine, has been linked to preeclampsia in humans, and is known to regulate T-cell activity and an endothelial-derived relaxing factor. To test the hypothesis that IDO is causally involved in the pathogenesis of preeclampsia, mice deficient for IDO (IDO-KO) were generated on a C57BL/6 background. IDO-KO and wild-type C57BL/6 mice were bred, and preeclampsia phenotypes were evaluated during pregnancy. Pregnant IDO-KO mice exhibited pathognomonic renal glomerular endotheliosis, proteinuria, pregnancy-specific endothelial dysfunction, intrauterine growth restriction, and mildly elevated blood pressure compared to wild-type mice. Together these findings highlight an important role for IDO in the generation of phenotypes typical of preeclampsia. Loss of IDO function may represent a risk factor for the development of preeclampsia. By extension, increased IDO activity, reductions in IDO reactants, or increases in IDO products may represent novel therapeutic approaches for this disorder.
    01/2015; 3(1). DOI:10.14814/phy2.12257
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    • "To date the tolerogenic function has been attributed to the induction of T regulatory cells (44, 53–59). Release of pDC-derived IL-10 and expression of IDO, PD-L1, and ICOS-L represent the mainstay for Treg induction (51, 54, 55, 57, 60–67) (Figure 1A, right panel). Furthermore, pDC effector function is subject to strong regulation by the cellular environment (43, 44, 60, 68–70): while TGFβ exposure promotes pDC-derived secretion of high levels of IL-6 and development of Th17 cells (71), soluble factors released from macrophages exposed to apoptotic cells prime pDC for Treg induction (52). "
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    ABSTRACT: Plasmacytoid dendritic cells (pDC) are a rare subset of leukocytes equipped with Fcγ and Fcε receptors, which exert contrary effects on sensing of microbial nucleic acids by endosomal Toll-like receptors. In this article, we explain how pDC contribute to the immune response to Staphylococcus aureus. Under normal circumstances the pDC participates in the memory response to the pathogen: pDC activation is initiated by uptake of staphylococcal immune complexes with IgG or IgE. However, protein A-expressing S. aureus strains additionally trigger pDC activation in the absence of immunoglobulin. In this context, staphylococci exploit the pDC to induce antigen-independent differentiation of IL-10 producing plasmablasts, an elegant means to propagate immune evasion. We further discuss the role of type I interferons in infection with S. aureus and the implications of these findings for the development of immune based therapies and vaccination.
    Frontiers in Immunology 05/2014; 5:238. DOI:10.3389/fimmu.2014.00238.
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    • "Indoleamine 2,3-dioxygenase (IDO) has emerged as a pivotal modulator/regulator of the immune response [13], [28], [34]. IDO is a heme-containing cytosolic enzyme that is the rate limiting catalyst to the metabolism of the essential amino acid tryptophan within the kynurenine pathway [15], [16]. "
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    ABSTRACT: Ischemia-Reperfusion (IR) injury of limb remains a significant clinical problem causing secondary complications and restricting clinical recovery, despite rapid restoration of blood flow and successful surgery. In an attempt to further improve post ischemic tissue repair, we investigated the effect of a local administration of bone marrow derived stem cells (BMDSCs) in the presence or absence of immune-regulatory enzyme, IDO, in a murine model. A whole limb warm ischemia-reperfusion model was developed using IDO sufficient (WT) and deficient (KO) mice with C57/BL6 background. Twenty-four hours after injury, 5×105 cells (5×105 cells/200 µL of PBS solution) BMDSCs (Sca1 + cells) were injected intramuscularly while the control group received just the vehicle buffer (PBS). Forty-eight to seventy-two hours after limb BMDSC injection, recovery status including the ratio of intrinsic paw function between affected and normal paws, general mobility, and inflammatory responses were measured using video micrometery, flow cytometry, and immunohistochemistry techniques. Additionally, MRI/MRA studies were performed to further study the inflammatory response between groups and to confirm reconstitution of blood flow after ischemia. For the first time, our data, showed that IDO may potentially represent a partial role in triggering the beneficial effects of BMDSCs in faster recovery and protection against structural changes and cellular damage in a hind limb IR injury setting (P = 0.00058).
    PLoS ONE 04/2014; 9(4):e95720. DOI:10.1371/journal.pone.0095720 · 3.23 Impact Factor
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