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: 13.77). 10/2007; 117(9):2570-82. DOI: 10.1172/JCI31911
Source: PubMed

ABSTRACT 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, Aug 22, 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.
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    • "Although a role for other DC subsets in PSA function cannot be ruled out, our results indicate that PSA's effect on PDCs, with consequent augmentation of Treg function, represents a central hostmicrobial strategy in the gut that limits the extent and severity of inflammatory diseases. Molecular mediators in murine and human PDCs that reportedly generate Tregs include ICOSL, IDO, retinoic acid, CD40L, D-like ligand 4 (a Notch ligand), and MHCII (Chen et al., 2008; Colvin et al., 2009; Fallarino et al., 2004; Irla et al., 2010; Ito et al., 2007; Kassner et al., 2010; Lombardi et al., 2012; Manches et al., 2008; Martín-Gayo et al., 2010; Sharma et al., 2007). "
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    • "The ensuing tryptophan depletion leads to the inhibition of T cell activation and expansion (Grohmann & Bronte 2010, Kushwah & Hu 2010). In addition, DCs that express IDO can stimulate the cellular general control non-depressible 2 kinase-dependent stress response in naïve and mature T cells and in functionally quiescent T regulatory cells, leading to active bystander suppression (Fallarino et al. 2006, Sharma et al. 2007). These mechanisms have broad implications in the study of immunological responses and tolerance under conditions as diverse as cancer, graft rejection and au- toimmunity. "
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