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 5

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Antigen-specific anergy induced by adoptive transfer of TDLN DCs. (A) T ...
Antigen-specific anergy induced by adoptive transfer of TDLN DCs. (A) T cell unresponsiveness following adoptive transfer was not due to carry-over of IDO-mediated suppression, as shown by the lack of effect of 1MT when added to the recall MLRs. Priming of CBA+BM3 recipients was with TDLN DCs or normal C57BL/6 DCs, as in the previous figures. (B) Anergic BM3 cells are rescued by exogenous IL-2. CBA+BM3 recipients were primed with TDLN DCs, and BM3 T cells were sorted from draining LNs based on clonotypic TCR expression versus CD8. Recall MLRs were performed using these purified BM3 responders and irradiated C57BL/6 spleen cell stimulators, with or without the addition of mitogenic anti-CD3 antibody, recombinant IL-2, or PMA/ionomycin to the MLRs, as shown. (C) CBA+BM3 hosts were primed with TDLN DCs, and then anergic BM3 T cells (clonotype-positive, CD8+) were sorted and tested for responsiveness to irradiated C57BL/6 spleen cells, with or without anti-CD3 antibody. In contrast, the unfractionated host CD8+ population from the same LN showed good response to mitogen. (D) Response to third-party BALB/c antigens (irradiated BALB/c splenocytes, 5-day MLR) was intact in CBA+BM3 recipients primed with TDLN DCs, compared with normal CBA control mice.