Differential IL‐10 production by DCs determines the distinct adjuvant effects of LPS and PTX in EAE induction

Abstract

Pertussis toxin (PTX) is used as an adjuvant to induce EAE in mice as a model of MS. Although LPS and PTX are similar in their ability to mature dendritic cells (DCs) and in their adjuvant properties, here we demonstrate that LPS does not induce EAE development. We also demonstrate that DCs treated with PTX (PTX-DCs) are able to induce EAE, whereas DCs treated with LPS (LPS-DCs) fail to induce EAE. We determine that a key difference between LPS-DCs and PTX-DCs is that LPS-DCs produce larger amounts of IL-10. IL-10−/− -DCs treated with LPS promote stronger IFN-γ and IL-17 production and T-cell proliferation than WT DCs treated with LPS in a coculture system. Finally, we demonstrate that EAE can be successfully induced when IL-10 −/− -DCs treated with LPS are used as an adjuvant, whereas the use of PTX-DCs overexpressing IL-10 as an adjuvant markedly controls EAE development. These results indicate that the inability of LPS to induce EAE is based on the induction of high levels of IL-10 in the targeted DCs, providing insight into the mechanisms responsible for the induction of EAE.Keywords: Dendritic cells r EAE r IL-10 r LPS r Pertussis toxin (PTX)Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionMS is a chronic autoimmune disease of the CNS. MS is characterized by inflammation, demyelination, and axonal pathology and is thought to occur in genetically predisposed individuals following exposure to an environmental trigger that activates myelin-specific pathogenic T cells that can cross the blood-brain barrier. EAE is Correspondence: Prof. Bing Sun e-mail: bsun@sibs.ac.cn; Yong-Jun.Liu@BaylorHealth.edu a mouse model for studying MS. MS and EAE were previously thought to be mediated by Th1 cells; however, numerous recent studies have provided strong evidence that IL-17-producing T cells play a dominant role in the pathogenesis of EAE [1][2][3]. Pertussis toxin (PTX) is an exotoxin that is produced by Bordetella pertussis. PTX blocks chemokine receptors such as CXCR4 and CCR5. PTX treatment causes a decrease in CXCR4 * These authors contributed equally to this work.C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2014. 44: 1352-1362 Cellular immune response 1353 surface expression, inhibits G protein associated signaling, and blocks stromal cell derived factor 1 alpha mediated chemotaxis by activating the TCR signaling network [4]. However, the detailed mechanism by which PTX blocks CCR5 is unclear, although receptor crosstalk between an unknown PTX receptor and chemokine receptors has been suggested [4]. PTX has been widely used as an adjuvant to induce Th1/Th17-mediated organ-specific autoimmune diseases in animal models, including experimental autoimmune uveitis (EAU) and EAE. PTX has profound effects on the immune system and is thought to induce EAE by facilitating the "opening" of the blood-brain barrier [5,6]. PTX is also an adjuvant that acts on dendritic cells (DCs) to induce DCs activation, IL-12 ...

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