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 2

SOCS1-silenced DCs induced pathological autoimmune responses.

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SOCS1-silenced DCs induced pathological autoimmune responses. (A) TRP2-s...
(A) TRP2-specific CTL responses induced by SOCS1-silenced DCs. Mice were immunized with TRP2-pulsed (50 μg/ml), LV-transduced WT, or IL-12p35–KO DCs with LPS-induced maturation (100 ng/ml) ex vivo. The mice were then stimulated 0, 1 (day 1), or 3 times (days 1, 4, and 7) i.p. with LPS (30 μg/mouse/injection). Percentages of TRP2-tetramer-PE–positive T cells in the gated CD8+ T cells of splenocytes in mice 2 weeks after immunization are shown from 1 of 3 independent experiments. P < 0.01, GFP-siRNA DCs versus SOCS1-siRNA DCs. (B) Representative autoimmune vitiligo of mice 3 months after immunization with TRP2-pulsed LV-SOCS1-siRNA DCs, followed by LPS stimulation once or 3 times. (C) Duration of DCs in draining LNs. Groups of mice were immunized with LV-transduced DCs, and CD11c+ DCs isolated from the draining LNs (dLN) of the mice at different times were used for RT-PCR analysis of the transgene eYFP marker mRNA. GAPDH was used as internal control. Experiments were repeated twice with similar results. (D and E) Inhibition of preestablished B16 tumors by SOCS1-siRNA DCs. WT, CD4-KO, or CD8-KO C57BL/6 mice were inoculated s.c. with B16 tumor cells (2.5 × 105) and 3 days later were immunized via the rear foot pad with 1.5 × 106 TRP2 peptide–pulsed (50 μg/ml), LV-transduced DCs with ex vivo LPS maturation (100 ng/ml). One day after DC transfer, in vivo LPS was administered i.p. (30 μg/mouse) 1 time. Tumor growth (n = 6 mice/group) and percent survival curves represent 1 of 3 independent experiments. P < 0.01, GFP-siRNA DCs compared with SOCS1-siRNA DCs.