Article

Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase

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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    • "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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