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 5

SOCS1 restricts the level and duration of IL-12 produced by DCs.

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WT DCs constitutively expressing IL-12 were insufficient to overcome sel...
(A and B) Levels of IL-12p40 (A) and IL-12p70 (B) secreted by DCs (5 × 105 cells/ml) in response to continuous stimulation with LPS (100 ng/ml) with or without plate-coated anti-CD40 mAb (1:1,000 dilution) for 24 hours from 1 of 3 independent experiments. All BM DCs were cultured with mGM-CSF (20 ng/ml) in the presence or absence of mIL-4 (20 ng/ml). *P < 0.01 versus SOCS1-siRNA DCs. (C). Kinetics of IL-12p70 production by DCs (5 × 105 cells/ml) in response to continuous stimulation with LPS (100 ng/ml) and anti-CD40 mAb for 0–72 hours from 1 of 3 independent experiments. All cells were cultured in the presence of both GM-CSF and IL-4. *P < 0.01 GFP-siRNA DCs versus SOCS1-siRNA DCs.