Global Inhibition of DC Priming Capacity in the Spleen of Self-Antigen Vaccinated Mice Requires IL-10

Abstract

Dendritic cells (DC) in the spleen are highly activated following intravenous vaccination with a foreign-antigen, promoting expansion of effector T cells, but remain phenotypically and functionally immature after vaccination with a self-antigen. Up-regulation or suppression of expression of a cohort of pancreatic enzymes 24–72 h post-vaccination can be used as a biomarker of stimulatory versus tolerogenic DC, respectively. Here we show, using MUC1 transgenic mice and a vaccine based on the MUC1 peptide, which these mice perceive as a self-antigen, that the difference in enzyme expression that predicts whether DC will promote immune response or immune tolerance is seen as early as 4–8 h following vaccination. We also identify early production of IL-10 as a predominant factor that both correlates with this early-time point and controls DC function. Pre-treating mice with an antibody against the IL-10 receptor prior to vaccination results in DC that up-regulate CD40, CD80, and CD86 and promote stronger IFNγ+ T cell responses. This study suggests that transient inhibition of IL-10 prior to vaccination could improve responses to cancer vaccines that utilize self-tumor antigens.

Dendritic Cell Control of Immune Responses

“…This article builds on the intriguing observation by the same group that immunization with foreign antigen induces a rapid upregulation of pancreatic enzymes in splenic DC that is correlated with the induction of immunity. The present article shows that immunization with a self-antigen fails to induce pancreatic enzymes and demonstrates a role for IL-10 in this phenomenon (6). Work by Kokulus et al (5) demonstrates the influence of mild chronic cold stress on the phenotype and function of DC in normal and tumorbearing mice.…”

“…The next four articles in this research topic are original research focusing on various aspects of DC function in vivo and in vitro (3)(4)(5)(6). DC maturation is induced by interaction with pathogenderived molecules such as LPS, but infections also induce production of a large number of cytokines.…”

Dendritic Cell Control of Immune Responses

“…This article builds on the intriguing observation by the same group that immunization with foreign antigen induces a rapid upregulation of pancreatic enzymes in splenic DC that is correlated with the induction of immunity. The present article shows that immunization with a self-antigen fails to induce pancreatic enzymes and demonstrates a role for IL-10 in this phenomenon ( 6 ). Work by Kokulus et al ( 5 ) demonstrates the influence of mild chronic cold stress on the phenotype and function of DC in normal and tumor-bearing mice.…”

“…The next four articles in this research topic are original research focusing on various aspects of DC function in vivo and in vitro ( 3 – 6 ). DC maturation is induced by interaction with pathogen-derived molecules such as LPS, but infections also induce production of a large number of cytokines.…”

“…In addition, this study emphasizes a systems approach to studying the complex effects of cytokine-induced DC maturation ( 3 ). DC play an important role in maintaining tolerance to self-antigens and the second article in this section describes the role of early IL-10 production in induction of tolerance to a self-antigen ( 6 ). This article builds on the intriguing observation by the same group that immunization with foreign antigen induces a rapid upregulation of pancreatic enzymes in splenic DC that is correlated with the induction of immunity.…”