Dendritic cells are recruited into the airway epithelium during the inflammatory response to a broad spectrum of stimuli

Abstract

A key rate-limiting step in the adaptive immune response at peripheral challenge sites is the transmission of antigen signals to T cells in regional lymph nodes. Recent evidence suggests that specialized dendritic cells (DC) fulfill this surveillance function in the resting state, but their relatively slow turnover in most peripheral tissues brings into question their effectiveness in signaling the arrival of highly pathogenic sources of antigen which require immediate mobilization of the full range of host defenses for maintenance of homeostasis. However, the present report demonstrates that recruitment of a wave of DC into the respiratory tract mucosa is a universal feature of the acute cellular response to local challenge with bacterial, viral, and soluble protein antigens. Consistent with this finding, we also demonstrate that freshly isolated respiratory mucosal DC respond in vitro to a variety of CC chemokines as well as complementary cleavage products and N-formyl-methionyl-leucine-phenylalanine. This suggests that rapid amplification of specific antigen surveillance at peripheral challenge sites is an integral feature of the innate immune response at mucosal surfaces, and serves as an "early warning system" to alert the adaptive immune system to incoming pathogens.

Figure 1

Quantitative cellular responses within tracheal epithelium during inflammation. Data shown are from representative experiments (⩾5 for each model); each point is a mean value derived from four to six animals. (A) Inhalation of aerosolized heat-killed M. catarrhalis produced an acute inflammatory reaction in which Ox6⁺ DC and RP3⁺ neutrophils were the only inflammatory cell type detected in the epithelium. Peak numbers were detected at 1 d after aerosol. (B) Live B. pertussis organisms inoculated intratracheally resulted in an influx of Ox6⁺ DC and RP3⁺ neutrophils with maximum cell numbers occurring at day 1. The T cell influx began at day 2 and peaked at day 4. (C ) Intranasal Sendai virus initiated a cellular response which commenced with an Ox6⁺ DC influx shortly after the earliest detection of intraepithelial Sendai virus nucleoprotein immunostaining at day 2 (C, arrow) and shortly before changes could be detected in other cell types. Maximum DC numbers were found at day 5, and coincided with maximal neutrophil and T cell numbers. (D) After intraperitoneal priming with ovalbumin and Al(OH)₆, animals were challenged 14 d later with an aerosol of ovalbumin and cellular changes within the epithelium measured. In this instance Ox6⁺ DC, eosinophil, and T cell numbers peaked at day 1 after challenge.

Figure 2

In vitro responses of respiratory tract DC to different chemotactic agents. Freshly prepared respiratory tract DC were assessed for responsiveness to a range of chemotactic agents in a 1 h chemotaxis assay, as detailed in Materials and Methods. Each data point represents results from an individual experiment, each of which included complementary cleavage products plus the medium control.