SOCS1 restricts dendritic cells’ ability to break self tolerance and induce antitumor immunity by regulating IL-12 production and signaling
Kevin Evel-Kabler, Xiao-Tong Song, Melissa Aldrich, Xue F. Huang, Si-Yi Chen
Kevin Evel-Kabler, Xiao-Tong Song, Melissa Aldrich, Xue F. Huang, Si-Yi Chen
View: Text | PDF
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

×

Figure 7

Persistent cytokine signaling in DCs is required to induce pathological autoimmune pathologies.

Options: View larger image (or click on image) Download as PowerPoint
Persistent cytokine signaling in DCs is required to induce pathological ...
(A) Inability to inhibit preestablished B16 tumors by IL-12p35–/–, IL-12Rβ2–/–, or IFN-γ–/– DCs. BM DCs derived from either WT, IL-12p35–/–, IFN-γ–/–, or IL-12Rβ2–/– mice were transduced with LV-SOCS1-siRNA or LV-GFP-siRNA. WT mice were inoculated s.c. with B16 tumor cells (2.5 × 105) and 3 days later were immunized with 1.5 × 106 TRP2-pulsed, matured DCs, followed by poly(I:C) stimulation i.p. on days 1, 3, and 5. Tumor growth curves (n = 6 mice/group) represent 1 of 3 independent experiments. (B) Reduced potency to induce CTL responses by SOCS1-silenced, IL-12Rβ2–/– DCs or IFN-γ–/– DCs. CD8+ T cells isolated from the pooled splenocytes of mice immunized with DCs derived from WT, IFN-γ–/–, IL-12p35–/–, or IL-12Rβ2–/– mice, followed by poly(I:C) stimulation 3 times, were subjected to IFN-γ ELISPOT assays. *P < 0.01 versus SOCS1-siRNA DCs. (C and D) In vivo IL-12 stimulation failed to enhance the potency of SOCS1-silenced, IL-12Rβ2–/– DCs. Mice were immunized once with WT or IL-12Rβ2–/– DCs (1.5 × 106/mouse) pulsed with TRP2 and matured with TNF-α, followed by IL-12 (i.p.) 3 times. Two weeks later, splenocytes or CD8+ T cells isolated from the pooled splenocytes were subjected to IFN-γ ELISPOT (C) and CTL assays against B16 tumor cells (D). *P < 0.01 versus SOCS1-siRNA DCs.