Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase.
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.
Sharma
Madhav D
MD
Department of Pediatrics, School of Medicine, Medical College of Georgia, Augusta, Georgia 30912, USA.
Baban
Babak
B
Chandler
Phillip
P
Hou
De-Yan
DY
Singh
Nagendra
N
Yagita
Hideo
H
Azuma
Miyuki
M
Blazar
Bruce R
BR
Mellor
Andrew L
AL
Munn
David H
DH
D000818:Animals; D018122:B7-1 Antigen / Q000378:metabolism; D060890:B7-H1 Antigen; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*; D006649:Histocompatibility Antigens / Q000276:immunology; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D008024:Ligands; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology*; D008207:Lymphatic Metastasis; D008213:Lymphocyte Activation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D009368:Neoplasm Transplantation; D010455:Peptides / Q000378:metabolism; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*
D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D006649:Histocompatibility Antigens; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D008024:Ligands; D008562:Membrane Glycoproteins; D010455:Peptides
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