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Tolerogenic pDCs: spotlight on Foxo3
Vincenzo Bronte
Vincenzo Bronte
Published March 23, 2011
Citation Information: J Clin Invest. 2011;121(4):1247-1250. https://doi.org/10.1172/JCI57190.
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Commentary

Tolerogenic pDCs: spotlight on Foxo3

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Abstract

Cancer creates a peculiar inflammatory environment enriched for transcription factors with a negative influence on adaptive immunity. In this issue of the JCI, Watkins and colleagues identify Foxo3 as a master regulator of the tolerogenic program in tumor-associated, plasmacytoid DCs (pDCs). Foxo3 enables pDCs to induce tolerance in tumor antigen-specific CD8+ T cells, turning them into regulatory lymphocytes capable of inhibiting nearby CD8+ T lymphocytes. Provision of tumor-specific CD4+ T helper cells interrupts this circuit by inhibiting Foxo3 expression and fully licensing the antigen-presenting ability of pDCs. These data identify a new target for therapeutic intervention and provide insight into the transcription factor interplay in myeloid cells recruited to the cancer microenvironment.

Authors

Vincenzo Bronte

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Figure 1

Interplay among leukocytes infiltrating prostate cancers.

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Interplay among leukocytes infiltrating prostate cancers.
(A) pDCs enter...
(A) pDCs enter the tumor environment, in which they can capture and present tumor antigens through class I (MHC I) and class II (MHC II) major histocompatibility molecules to CD8+ and CD4+ T cells specific for the antigen. Environmental signals drive the expression of Foxo3 that in turn controls the de novo synthesis of the amino acid–metabolizing enzymes IDO and ARG1, the cytokine TGF-β, and the surface inhibitory molecule PD-L1. After interaction with CD8+ T cells, Foxo3-expressing pDCs enforce conversion of CD8+ T cells into Tregs, which then block proliferation and effector functions on nearby CD8+ T lymphocytes, recognizing either the same or other tumor antigens. (B) This immunosuppressive network is disrupted by the generation of tumor-antigen specific CD4+ T cells that engage pDCs, turn off Foxo3, and make pDCs capable of fully stimulating CD8+ T cells, allowing their proliferation and acquisition of effector function, as highlighted by the recovered ability to release IFN-γ and recognize cancer cells.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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