SOCS1 restricts dendritic cells’ ability to break self tolerance and induce antitumor immunity by regulating IL-12 production and signaling
Kevin Evel-Kabler, … , Xue F. Huang, Si-Yi Chen
Kevin Evel-Kabler, … , Xue F. Huang, Si-Yi Chen
Published January 4, 2006
Citation Information: J Clin Invest. 2006;116(1):90-100. https://doi.org/10.1172/JCI26169.
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Research Article Immunology

SOCS1 restricts dendritic cells’ ability to break self tolerance and induce antitumor immunity by regulating IL-12 production and signaling

Abstract

DC-based tumor vaccine research has largely focused on enhancing DC maturation/costimulation and antigen presentation in order to break tolerance against self tumor-associated antigens. DC immunization can activate autoreactive T cells but rarely causes autoimmune pathologies, indicating that self tolerance at the host level is still maintained in the vaccinated hosts. This study in mice reveals a novel regulatory mechanism for the control of self tolerance at the host level by DCs through the restriction of positive cytokine feedback loops by cytokine signaling inhibitor SOCS1. The study further finds the requirement of persistent antigen presentation by DCs for inducing pathological autoimmune responses against normal tissues and tumor, which can be achieved by silencing SOCS1 to unleash the unbridled signaling of IL-12 and the downstream cytokine cascade. However, the use of higher-affinity self peptides, enhancement of DC maturation, and persistent stimulation with cytokines or TLR agonists fail to break tolerance and induce pathological antitumor immunity. Thus, this study indicates the necessity of inhibiting SOCS1, an antigen presentation attenuator, to break self tolerance and induce effective antitumor responses.

Authors

Kevin Evel-Kabler, Xiao-Tong Song, Melissa Aldrich, Xue F. Huang, Si-Yi Chen

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Figure 8

Enhanced signaling and sensitivity of SOCS1-silenced DCs to autocrine/paracrine IL-12 stimulation.

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Enhanced signaling and sensitivity of SOCS1-silenced DCs to autocrine/pa...
(A) Western blotting of Stat4 and phosphorylated Stat4 (pStat4) in LV-transduced BM-DCs (1 × 106 cells/ml) after stimulation with LPS and anti-CD40 mAb for 0, 24, 48, or 72 hours. BM DCs were cultured in the presence of GM-CSF and IL-4. (B) IFN-γ levels secreted by LV-transduced, TNF-α–matured WT DCs (1 × 106 cells/ml) 6, 24, or 48 hours after stimulation with recombinant IL-12 (20 ng/ml) from 1 of 3 independent experiments. *P < 0.01 versus SOCS1-siRNA DCs. (C) Levels of IL-12p70 secreted by transduced DCs (1 × 106 cells/ml) derived from WT or IL-12Rβ2–/– mice at different times after stimulation with TLR agonist (LPS, 100 ng/ml) from 1 of 3 independent experiments. All cells were cultured in the presence of GM-CSF and IL-4. *P < 0.01 versus WT SOCS1-siRNA DCs.