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Background  Nitrogen dioxide (NO 2 ) is an air pollutant associated with poor respiratory health, asthma exacerbation, and an increased likelihood of inhalational allergies. NO 2  is also produced endogenously in the lung during acute inflammatory responses. NO 2  can function as an adjuvant, allowing for allergic sensitization to an innocuous inhaled antigen and the generation of an antigen-specific Th2 immune response manifesting in an allergic asthma phenotype. As CD11c +  antigen presenting cells are considered critical for naïve T cell activation, we investigated the role of CD11c +  cells in NO 2 -promoted allergic sensitization.    Methods  We systemically depleted CD11c +  cells from transgenic mice expressing a simian diphtheria toxin (DT) receptor under of control of the CD11c promoter by administration of DT. Mice were then exposed to 15 ppm NO 2  followed by aerosolized ovalbumin to promote allergic sensitization to ovalbumin and were studied after subsequent inhaled ovalbumin challenges for manifestation of allergic airway disease. In addition, pulmonary CD11c +  cells from wildtype mice were studied after exposure to NO 2  and ovalbumin for cellular phenotype by flow cytometry and  in vitro  cytokine production.    Results  Transient depletion of CD11c +  cells during sensitization attenuated airway eosinophilia during allergen challenge and reduced Th2 and Th17 cytokine production. Lung CD11c +  cells from wildtype mice exhibited a significant increase in MHCII, CD40, and OX40L expression 2 hours following NO 2  exposure. By 48 hours, CD11c + MHCII +  DCs within the mediastinal lymph node (MLN) expressed maturation markers, including CD80, CD86, and OX40L. CD11c + CD11b -  and CD11c + CD11b +  pulmonary cells exposed to NO 2   in vivo  increased uptake of antigen 2 hours post exposure, with increased ova-Alexa 647 +  CD11c + MHCII +  DCs present in MLN from NO 2 -exposed mice by 48 hours. Co-cultures of ova-specific CD4 +  T cells from naïve mice and CD11c +  pulmonary cells from NO 2 -exposed mice produced IL-1, IL-12p70, and IL-6  in vitro  and augmented antigen-induced IL-5 production.    Conclusions  CD11c +  cells are critical for NO 2 -promoted allergic sensitization. NO 2  exposure causes pulmonary CD11c +  cells to acquire a phenotype capable of increased antigen uptake, migration to the draining lymph node, expression of MHCII and co-stimulatory molecules required to activate naïve T cells, and secretion of polarizing cytokines to shape a Th2/Th17 response.

NO2 inhalation induces maturation of pulmonary CD11c+ cells that promote antigen-specific CD4+ T cell polarization