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Fungal Proteases Induce Th2 Polarization through Limited Dendritic Cell Maturation and Reduced Production of IL-12

Salah-Eddine Lamhamedi-Cherradi^1,*,, Rachel Elizabeth Martin^*, Tomoki Ito, Farrah Kheradmand^¶, David Brian Corry^¶, Yong-Jun Liu and Matthew Moyle^1,

^* Tanox, Houston, TX 77025; Cell Genesys, San Francisco, CA 94080; Spaltudaq Corporation, Seattle, WA 98102; Department of Immunology and Center of Cancer Immunology Research, University of Texas, M.D. Anderson Cancer Center; and ^¶ Departments of Medicine and Immunology, Baylor College of Medicine, Houston, TX 77030

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- 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- 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.

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¹ Address correspondence and reprint requests to Dr. Salah-Eddine Lamhamedi-Cherradi, Cell Genesys Inc., 500 Forbes Boulevard, South San Francisco, CA 94080. E-mail address: salah.cherradi{at}cellgenesys.com or Dr. Matthew Moyle, Spaltudaq Corporation, Seattle Life Sciences Building, 1124 Columbia Street, Suite 300, Seattle, WA 98104. E-mail address: mmoyle{at}spaltudaq.com

² Abbreviations used in this paper: DC, dendritic cell; rh, recombinant human; AP, Aspergillus oryzae-derived protease; poly(I:C), polyinosinic-polycytidylic acid; C_t, threshold cycle; iDC, immature DC.