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Extracellular Acidosis Triggers the Maturation of Human Dendritic Cells and the Production of IL-12¹

Diego Martínez^*, Mónica Vermeulen^*, Erika von Euw^,, Juan Sabatté^*, Julian Maggíni^*, Ana Ceballos^*, Analía Trevani^*, Karen Nahmod^*, Gabriela Salamone^*, Marcela Barrio, Mirta Giordano^*, Sebastian Amigorena and Jorge Geffner^2,*

^* Institute of Hematologic Research, National Academy of Medicine, National Reference Center for AIDS, and Department of Microbiology, Buenos Aires University School of Medicine, Centro de Investigaciones Oncológicas-FUCA, Fundación Instituto Leloir, Buenos Aires, Argentina; and Institut National de la Sante et de la Recherche Medicale, Unite 365, Immunite et Cancer, Institut Curie, Paris, France

Although the development of an acidic tissue environment or acidosis is a hallmark of inflammatory processes, few studies analyze the effect of extracellular pH on immune cells. We have previously shown that exposure of murine dendritic cells (DCs) to pH 6.5 stimulates macropinocytosis and cross-presentation of extracellular Ags by MHC class I molecules. We report that the transient exposure of human DCs to pH 6.5 markedly increases the expression of HLA-DR, CD40, CD80, CD86, CD83, and CCR7 and improves the T cell priming ability of DCs. Incubation of DCs at pH 6.5 results in the activation of the PI3K/Akt and the MAPK pathways. Using specific inhibitors, we show that the maturation of DCs induced by acidosis was strictly dependent on the activation of p38 MAPK. DC exposure to pH 6.5 also induces a dramatic increase in their production of IL-12, stimulating the synthesis of IFN-, but not IL-4, by Ag-specific CD4⁺ T cells. Interestingly, we find that suboptimal doses of LPS abrogated the ability of pH 6.5 to induce DC maturation, suggesting a cross-talk between the activation pathways triggered by LPS and extracellular protons in DCs. We conclude that extracellular acidosis in peripheral tissues may contribute to the initiation of adaptive immune responses by DCs, favoring the development of Th1 immunity.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires University School of Medicine, and Agencia Nacional de Promoción Científica y Tecnológica, Argentina.

² Address correspondence and reprint requests to Dr. Jorge Geffner, Departamento de Inmunología, Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina, Pacheco de Melo 3081, 1425 Buenos Aires, Argentina. E-mail address: geffnerj{at}fibertel.com.ar

³ Abbreviations used in this paper: DC, dendritic cell; TT, tetanus toxoid; fluo-3-AM, fluo-3-acetoxymethyl ester; [Ca²⁺]_i, intracellular Ca²⁺ concentration.

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