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
Source: PubMed


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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    • "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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    • "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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    • "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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