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.
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 3

Effects of SOCS1 silencing on antigen presentation by DCs.

Options: View larger image (or click on image) Download as PowerPoint
The role of IL-12 produced by SOCS1-silenced DCs in breaking self tolera...
(A) Inhibition of preestablished B16 tumor by SOCS1-siRNA DC immunization with TRP2 peptides of different affinities. WT C57BL/6 mice were inoculated s.c. with B16 tumor cells (2.5 × 105) and 3 days later were immunized with 1.5 × 106 TRP2 peptide–pulsed (50 μg/ml; TRP2a or TRP2b), 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 curves (n = 6 mice/group) represent 1 of 3 independent experiments. P < 0.01, GFP-siRNA DC compared with SOCS1-siRNA DCs. (B). CD8+ T cell responses induced by SOCS1-siRNA DCs with different TRP2 peptides. CD8+ T cells isolated from the pooled splenocytes of immunized mice (2–3 mice) were subjected to IFN-γ ELISPOT assays stimulated with TRP2a or TRP2b peptide (10 μg/ml). An irrelevant peptide derived from ovalbumin was used as a negative control. *P < 0.01 versus SOCS1-siRNA DC plus TRP2a; **P < 0.01 versus SOCS1-siRNA DC plus TRP2a.