title: Fungal proteases induce Th2 polarization through limited dendritic cell maturation and reduced production of IL-12.
abstract: Allergens are capable of polarizing the T cell immune response toward a Th2 cytokine profile in a process that is mediated by dendritic cells (DCs). Proteases derived from Aspergillus species (Aspergillus proteases; AP) have been shown to induce a Th2-like immune response when administered directly to the airway and without adjuvant or prior priming immunizations at sites remote from the lung in models of allergic airway disease. To explore mechanisms that underlie the Th2 immune response, we have investigated the effect of AP on DC function. We found that human DCs derived from CD14(+) monocytes from healthy donors underwent partial maturation when incubated with AP. Naive allogeneic T cells primed with AP-activated DCs proliferated and displayed enhanced production of IL-4 and reduced expression of IFN-gamma as compared with naive T cells primed with LPS-activated DCs. Global gene expression analysis of DCs revealed relatively low expression of IL-12p40 in AP-activated DCs as compared with those activated by LPS, and this was confirmed at the protein level by ELISA. Exogenous IL-12p70 added to cocultures of DCs and T cells resulted in reduced IL-4 and increased IFN-gamma expression when DCs were activated with AP. When the proteolytic activity of AP was neutralized by chemical inactivation it failed to up-regulate costimulatory molecules on DCs, and these DCs did not prime a Th2 response in naive T cells. These findings provide a mechanism for explaining how proteolytically active allergens could preferentially induce Th2 responses through limited maturation of DCs with reduced production of IL-12.
authors.affiliation: Tanox, Houston, TX 77025, USA. salah.cherradi@cellgenesys.com
authors.forename: Salah-Eddine
authors.initials: SE
authors.lastname: Lamhamedi-Cherradi
authors.forename: Rachel Elizabeth
authors.initials: RE
authors.lastname: Martin
authors.forename: Tomoki
authors.initials: T
authors.lastname: Ito
authors.forename: Farrah
authors.initials: F
authors.lastname: Kheradmand
authors.forename: David Brian
authors.initials: DB
authors.lastname: Corry
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Liu
authors.forename: Matthew
authors.initials: M
authors.lastname: Moyle
mesh_terms: D000485:Allergens / Q000276:immunology* / Q000378:metabolism; D001230:Aspergillus / Q000201:enzymology / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005656:Fungal Proteins / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D053762:Interleukin-12 Subunit p40 / Q000096:biosynthesis / Q000276:immunology*; D015847:Interleukin-4 / Q000096:biosynthesis / Q000276:immunology; D018950:Lipopolysaccharide Receptors / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008954:Models, Biological; D010447:Peptide Hydrolases / Q000276:immunology* / Q000378:metabolism; D012130:Respiratory Hypersensitivity / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism
chemical_list: D000485:Allergens; D005656:Fungal Proteins; C500879:IL12B protein, human; C508598:IL4 protein, human; D053762:Interleukin-12 Subunit p40; D018950:Lipopolysaccharide Receptors; D015847:Interleukin-4; D007371:Interferon-gamma; D010447:Peptide Hydrolases