Cholera toxin adjuvant promotes a balanced Th1/Th2/Th17 response independently of IL-12 and IL-17 by acting on Gsα in CD11b+ DCs

• Published in: Mucosal immunology Vol. 8; no. 4; pp. 815 - 827
• Main Authors: Mattsson, J, Schön, K, Ekman, L, Fahlén-Yrlid, L, Yrlid, U, Lycke, N Y
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-07-2015
• Subjects: 631/250/347; 631/250/590/2291; 631/326/41/1319; 631/92/609; adjuvant; Allergology; Animals; Antibodies; Biomedical and Life Sciences; Biomedicine; CD11b Antigen - genetics; CD11b Antigen - metabolism; cholera toxin; Cholera Toxin - administration & dosage; Cholera Toxin - immunology; dendritic cells; Dendritic Cells - immunology; Dendritic Cells - metabolism; Gastroenterology; Gene Expression; Gs-alpha; GTP-Binding Protein alpha Subunits, Gs - genetics; GTP-Binding Protein alpha Subunits, Gs - metabolism; Immunization; Immunologi inom det medicinska området; Immunology; Immunology in the medical area; Interleukin-12 - genetics; Interleukin-12 - metabolism; Interleukin-17 - genetics; Interleukin-17 - metabolism; Mice; Mice, Knockout; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocytes, Helper-Inducer - immunology; T-Lymphocytes, Helper-Inducer - metabolism; Th1 Cells - immunology; Th1 Cells - metabolism; Th17; Th17 Cells - immunology; Th17 Cells - metabolism; Th2 Cells - immunology; Th2 Cells - metabolism; Time Factors
• ISSN: 1933-0219; 1935-3456; 1935-3456
• DOI: 10.1038/mi.2014.111

Despite an extensive literature on the mechanism of action of cholera toxin (CT), we still lack critical information about how the toxin acts as an adjuvant and, especially, which dendritic cells (DCs) are the target cells. Although a T helper type 2 (Th2)-skewing effect of CT is most commonly reported, effective priming of Th17 cells as well as suppression of Th1 responses are well documented. However, the ability of CT to block interferon regulatory factor 8 (IRF8) function and interleukin (IL)-12 production in DCs, which blocks CD8α DC and Th1 cell development, is inconsistent with priming of Th1 and CD8 T cells in many other reports. This prompted us to investigate the adjuvant effect of CT in wild-type, IL-12p40−/−, Batf3−/−, and IL-17A−/− mice and in mice that selectively lack the Gsα target protein for CT adenosine diphosphate (ADP)-ribosylation in DCs. We found that CT promoted Th1 priming independently of IL-12, and whereas Th2 and also Th17 responses were augmented, the gut IgA responses did not require IL-17A. Adjuvanticity was intact in Batf3−/− mice, lacking CD8α
+
DCs, but completely lost in mice with Gsα-deficient CD11c cells. Thus, our data demonstrate that the adjuvant effect requires Gsα expression in CD11b
+
DCs, and that priming of mucosal IgA and CD4 T cells appears unbiased and is independent of IL-12 and IL-17A.