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Title: Deficiency in calcium-binding protein S100A4 impairs the adjuvant action of cholera toxin
Authors: Sun, JB
Holmgren, J
Larena, M
Terrinoni, M
Fang, Y
Bresnick, AR
Xiang, Z 
Keywords: Adjuvant
Cholera toxin
Dendritic cells
Germinal center
Issue Date: 11-Sep-2017
Publisher: Frontiers Research Foundation
Source: Frontiers in immunology, 11 Sept. 2017, v. 8, 1119, p. 1-10 How to cite?
Journal: Frontiers in immunology 
Abstract: The calcium-binding protein S100A4 has been described to promote pathological inflammation in experimental autoimmune and inflammatory disorders and in allergy and to contribute to antigen presentation and antibody response after parenteral immunization with an alum-adjuvanted antigen. In this study, we extend these findings by demonstrating that mice lacking S100A4 have a defective humoral and cellular immune response to mucosal (sublingual) immunization with a model protein antigen [ovalbumin (OVA)] given together with the strong mucosal adjuvant cholera toxin (CT), and that this impairment is due to defective adjuvant-stimulated antigen presentation by antigen-presenting cells. In comparison to wild-type (WT) mice, mice genetically lacking S100A4 had reduced humoral and cellular immune responses after immunization with OVA plus CT, including a complete lack of detectable germinal center reaction. Further, when stimulated in vitro with OVA plus CT, S100A4-/- dendritic cells (DCs) showed impaired responses in several CT-stimulated immune regulatory molecules including the co-stimulatory molecule CD86, inflammasome-associated caspase-1 and IL-1ß. Coculture of OVA-specific OT-II T cells with S100A4-/- DCs that had been pulse incubated with OVA plus CT resulted in impaired OT-II T cell proliferation and reduced production of Th1, Th2, and Th17 cytokines compared to similar cocultures with WT DCs. In accordance with these findings, transfection of WT DCs with S100A4-targeting small interfering RNA (siRNA) but not mock-siRNA resulted in significant reductions in the expression of caspase-1 and IL-1ß as well as CD86 in response to CT. Importantly, also engraftment of WT DCs into S100A4-/- mice effectively restored the immune response to immunization in the recipients. In conclusion, our results demonstrate that deficiency in S100A4 has a strong impact on the development of both humoral and cellular immunity after mucosal immunization using CT as adjuvant.
ISSN: 1664-3224
EISSN: 1664-3224
DOI: 10.3389/fimmu.2017.01119
Rights: Copyright © 2017 Sun, Holmgren, Larena, Terrinoni, Fang, Bresnick and Xiang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) ( The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
The following publication Sun J-B, Holmgren J, Larena M, Terrinoni M, Fang Y, Bresnick AR and Xiang Z (2017) Deficiency in Calcium-Binding Protein S100A4 Impairs the Adjuvant Action of Cholera Toxin. Front. Immunol. 8:1119,1-10 is available at
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