Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes
David H. Munn, … , Pandelakis A. Koni, Andrew L. Mellor
David H. Munn, … , Pandelakis A. Koni, Andrew L. Mellor
Published July 15, 2004
Citation Information: J Clin Invest. 2004;114(2):280-290. https://doi.org/10.1172/JCI21583.
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Article Oncology

Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes

Abstract

One mechanism contributing to immunologic unresponsiveness toward tumors may be presentation of tumor antigens by tolerogenic host APCs. We show that mouse tumor-draining LNs (TDLNs) contained a subset of plasmacytoid DCs (pDCs) that constitutively expressed immunosuppressive levels of the enzyme indoleamine 2,3-dioxygenase (IDO). Despite comprising only 0.5% of LN cells, these pDCs in vitro potently suppressed T cell responses to antigens presented by the pDCs themselves and also, in a dominant fashion, suppressed T cell responses to third-party antigens presented by nonsuppressive APCs. Adoptive transfer of DCs from TDLNs into naive hosts created profound local T cell anergy, specifically toward antigens expressed by the transferred DCs. Anergy was prevented by targeted disruption of the IDO gene in the DCs or by administration of the IDO inhibitor drug 1-methyl-D-tryptophan to recipient mice. Within the population of pDCs, the majority of the functional IDO-mediated suppressor activity segregated with a novel subset of pDCs coexpressing the B-lineage marker CD19. We hypothesize that IDO-mediated suppression by pDCs in TDLNs creates a local microenvironment that is potently suppressive of host antitumor T cell responses.

Authors

David H. Munn, Madhav D. Sharma, Deyan Hou, Babak Baban, Jeffrey R. Lee, Scott J. Antonia, Jane L. Messina, Phillip Chandler, Pandelakis A. Koni, Andrew L. Mellor

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Figure 2

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Suppression of T cell responses by TDLN cells. (A) Cells from TDLNs and ...
Suppression of T cell responses by TDLN cells. (A) Cells from TDLNs and contralateral LNs (CLN) were harvested from mice with B78H1–GM-CSF tumors (day 14), and used as stimulators in MLRs (stimulator cell number in parentheses; responder BM3 T cells at 5 × 104 per well). Mixing experiments (right) demonstrated dominant suppression by the TDLN cells. (B) TDLN cells were sorted by four-color flow cytometry into pDCs (<1%), Treg’s (2–3%), and all other cells (95–97%), using the markers shown. Each fraction was used as stimulator cells in MLRs, adding the number of cells that would have been present in 5 × 104 of the original TDLN population (thus, the pDCs were added at approximately 500 cells per well). All MLRs received 5 × 104 BM3 responders. For mixing experiments, the sorted fractions were mixed in the same ratio in which they were present in the original unsorted preparation. (C) Suppression by pDCs is mediated by IDO. TDLN cells were sorted as described for B. The pDCs and “other” fraction were used as stimulators in MLRs (BM3 responders), with and without the IDO inhibitor 1MT. Left: TDLN cells taken from a wild-type (IDO-sufficient) host, showing suppression by pDCs, which was blocked by 1MT (arrows), and dominant suppression with mixing. Right: Tumors were grown in IDO-KO hosts, and the IDO-KO TDLN cells were harvested and assayed as at left. THY incorp., thymidine incorporation.