Article

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

Juntendo University, Edo, Tokyo, Japan
Journal of Clinical Investigation (Impact Factor: 13.22). 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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    • "This decrease in CD3 + T cells corresponded to a diminished infiltration of both CD8 + and CD4 + Teff cells (Figure 3B), but a notable increase in Foxp3 + Tregs (Figure 3B). Activation of Tregs in tumor models in vivo has previously been linked to IDO so this finding was not surprising (Sharma et al., 2007). There were also decreased percentages of CD19 + B cells, natural killer (NK) cells, and natural killer T cells (NKT) noted at the tumor site, but these differences did not reach statistical significance (Figures 3A and 3B). "
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    ABSTRACT: Indoleamine 2,3-dioxygenase (IDO) has been described as a major mechanism of immunosuppression in tumors, though the mechanisms of this are poorly understood. Here, we find that expression of IDO by tumor cells results in aggressive tumor growth and resistance to T-cell-targeting immunotherapies. We demonstrate that IDO orchestrates local and systemic immunosuppressive effects through recruitment and activation of myeloid-derived suppressor cells (MDSCs), through a mechanism dependent on regulatory T cells (Tregs). Supporting these findings, we find that IDO expression in human melanoma tumors is strongly associated with MDSC infiltration. Treatment with a selective IDO inhibitor in vivo reversed tumor-associated immunosuppression by decreasing numbers of tumor-infiltrating MDSCs and Tregs and abolishing their suppressive function. These findings establish an important link between IDO and multiple immunosuppressive mechanisms active in the tumor microenvironment, providing a strong rationale for therapeutic targeting of IDO as one of the central regulators of immune suppression.
    Full-text · Article · Sep 2015 · Cell Reports
    • "Recent studies further suggested that IDO can be expressed not only by macrophages but also by antigen presenting cells (dendritic cells), either constitutively or after induction. These cells are responsible for exerting immune tolerance through activation of regulatory T cells [64], suppressing the immune response of leucocytes. In the present study, the decreased lymphocyte recruitment to the infection focus may be indicative of such an immune tolerance state. "
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    ABSTRACT: Amino acids regulate key metabolic pathways important to immune responses and their nutritional supply may increase synthesis of immune-related proteins. The present study aimed to evaluate the effects of dietary supplementation of tryptophan and methionine on European seabass (Dicentrarchus labrax) cellular and humoral status. The immunomodulatory effects of tryptophan and methionine during an inflammatory insult was also evaluated after intraperitoneal injection with inactivated Photobacterium damselae subsp. piscicida (Phdp).
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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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