Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase
| Autor: | Bruce R. Blazar, Babak Baban, Hideo Yagita, Andrew L. Mellor, Nagendra Singh, Miyuki Azuma, De Yan Hou, Madhav D. Sharma, David H. Munn, Phillip Chandler |
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| Rok vydání: | 2007 |
| Předmět: |
Cellular differentiation
T cell Population chemical and pharmacologic phenomena Biology Ligands Lymphocyte Activation T-Lymphocytes Regulatory B7-H1 Antigen Mice Downregulation and upregulation Histocompatibility Antigens medicine Animals Humans Indoleamine-Pyrrole 2 3 -Dioxygenase IL-2 receptor education Indoleamine 2 3-dioxygenase education.field_of_study Membrane Glycoproteins FOXP3 Cell Differentiation hemic and immune systems Dendritic Cells General Medicine medicine.anatomical_structure Lymphatic Metastasis Immunology B7-1 Antigen Cancer research Lymph Nodes Peptides Neoplasm Transplantation Ex vivo Signal Transduction Research Article |
| Zdroj: | Journal of Clinical Investigation. 117:2570-2582 |
| ISSN: | 0021-9738 |
| DOI: | 10.1172/jci31911 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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