Consistent with their role in host defense, mature dendritic cells (DCs) from central lymphoid organs preferentially prime for T helper cell type 1 (Th1)-polarized immunity. However, the “default” T helper response at mucosal surfaces demonstrates Th2 polarity, which is reflected in the cytokine profiles of activated T cells from mucosal lymph nodes. This study on rat respiratory tract DCs (RTDCs) provides an explanation for this paradox. We demonstrate that freshly isolated RTDCs are functionally immature as defined in vitro, being surface major histocompatibility complex (MHC) II lo, endocytosishi, and mixed lymphocyte reactionlo, and these cells produce mRNA encoding interleukin (IL)-10. After ovalbumin (OVA)-pulsing and adoptive transfer, freshly isolated RTDCs preferentially stimulated Th2-dependent OVA-specific immunoglobulin (Ig)G1 responses, and antigen-stimulated splenocytes from recipient animals produced IL-4 in vitro. However, preculture with granulocyte/macrophage colony stimulating factor increased their in vivo IgG priming capacity by 2–3 logs, inducing production of both Th1- and Th2-dependent IgG subclasses and high levels of IFN-γ by antigen-stimulated splenocytes. Associated phenotypic changes included upregulation of surface MHC II and B7 expression and IL-12 p35 mRNA, and downregulation of endocytosis, MHC II processing– associated genes, and IL-10 mRNA expression. Full expression of IL-12 p40 required additional signals, such as tumor necrosis factor α or CD40 ligand. These results suggest that the observed Th2 polarity of the resting mucosal immune system may be an inherent property of the resident DC population, and furthermore that mobilization of Th1 immunity relies absolutely on the provision of appropriate microenvironmental costimuli.

SummaryImmunohistochemical analysis of challenge sites such as skin and the peritoneal cavity has identified neutrophils as virtually the sole cellular participants in acute bacterial inflammation, peak influx occurring 24-48 h in advance of mononuclear cell populations associated with adaptive immunity This study challenges the general applicability of this paradigm. We demonstrate here that the earliest detectable cellular response after inhalation ofMoraxdla catarrhalis organisms is the recruitment of putative class II major histocompatibflity complex-bearing dendritic cell (DC) precursors into the airway epithelium, the initial wave arriving in advance of the neutrophil influx. Unlike the neutrophils which rapidly transit into the airway lumen, the DC precursors remain within the epithelium during the acute inflammatory response where they differentiate, and develop the dendriform morphology typical of resident DC found in the normal epithelium. During the ensuing 48-h period, these cells then migrate to the regional lymph nodes. No comparable DC response was observed after epidermal or intraperitoneal challenge, and it may be that mucosal surfaces are unique in their requirement for rapid DC responses during acute inflammation. We hypothesize that the role of the DC influx during acute inflammation may be surveiUance for opportunistic viruses, and that this covert protective mechanism is operative at a restricted number of mucosal tissue sites. p revious reports from this laboratory have established the importance of dendritic cells (DC) as APC within normal lung tissue (1, 2), and have additionally shown that a functionally and morphologically identical DC population exists within the epithelial lining of the conducting airways of both humans (3) and rodents (4, 5), where they form a contiguous network analogous to the Langerhans cell (LC) population in the epidermis.We have also recently presented evidence that the density, distribution, and surface phenotype of airway DC populations reflects the level of stimulation provided by inhalation of airborne irritant stimuli (5). Moreover, brief exposure to aerosolized bacterial LPS was demonstrated to induce a transient increase (,o50%) in the density of airway intraepithelial DC during the 24-48-h period after exposure, suggesting active participation of DC in the acute inflammatory response (5). The present study sought to further elucidate the role of DC in acute inflammation in the airways, employing a much more potent inhaled stimulus in the form of whole bacteria. Materiah and MethodsAnimals. Specific pathogen-free (SPF) adult PVG rats were used in these experiments. They were barrier housed under dust-free conditions, as detailed previously (5).Aerosol Exposure The animals were exposed for 60 rain to an aerosol of heat-killed MoraxeUa catarrhalis organisms (clinical hospital isohte) suspended in normal saline at '~109 CFU/ml.Antibodies and Iraraunostaining. The mAbs Ox6 (Ia), Ox19 (CDS; pan T cell), Ox12 (r light chains; pan B cell) (6), and Ox 42 (~ cha...

APCs, including dendritic cells (DC), are central to Ag surveillance in the respiratory tract (RT). Research in this area is dominated by mouse studies on purportedly representative RT-APC populations derived from whole-lung digests, comprising mainly parenchymal tissue. Our recent rat studies identified major functional differences between DC populations from airway mucosal vs parenchymal tissue, thus seriously questioning the validity of this approach. We addressed this issue for the first time in the mouse by separately characterizing RT-APC populations from these two different RT compartments. CD11chigh myeloid DC (mDC) and B cells were common to both locations, whereas a short-lived CD11cneg mDC was unique to airway mucosa and long-lived CD11chigh macrophage and rapid-turnover multipotential precursor populations were predominantly confined to the lung parenchyma. Airway mucosal mDC were more endocytic and presented peptide to naive CD4+ T cells more efficiently than their lung counterparts. However, mDC from neither site could present whole protein without further maturation in vitro, or following trafficking to lymph nodes in vivo, indicating a novel mechanism whereby RT-DC function is regulated at the level of protein processing but not peptide loading for naive T cell activation.