Dendritic cells (DCs) have a pivotal role in the initiation and maintenance of immune responses. These cells are strategically located in the epithelium of tissues such as the skin, gut and lung, where they interface directly with the environment. DCs take up antigen at these surfaces and migrate to draining lymph nodes, where they provide naive T cells with a dynamic representation of the environment. Much has been learned about these important cells during the last several years, but several facets of DC biology are still poorly understood. For example, relatively few studies have addressed the impact of non-allergenic environmental agents on DC function and migration, and allergen sensitization. In part, this is because it has been difficult to sensitize animals through the airway. Recently, a method was described in which low levels of the bacterial product, lipopolysaccharide (LPS) were shown to act as an adjuvant in the airway to elicit effector immune responses. We are using this model to determine the effect of LPS and other environmental agents on allergen uptake, DC activation and migration to draining lymph nodes and allergen sensitization through the airway.? ? There are several ongoing projects within our lab that address the impact of the environment on various aspects of allergic pulmonary inflammation, including sensitization through the airway, and the maintenance of allergic inflammation in the lung. These projects are summarized as follows:? ? 1) Function of tlr4 in ongoing allergic inflammation. ? We have studied the effect of very low doses of LPS in models of both short term and long term allergen challenge. When challenged for short periods with allergen containing low levels of LPS, wild type and tlr4-deficient mice had similar responses. However, when challenged for periods of one week or longer, tlr4-deficient mice developed dramatically increased airway eosinophils, serum IgE and Th2 cytokines compared to similarly challenged, genetically-matched C57BL/6 mice. These findings show that low doses of endotoxin can have regulatory effects on allergic inflammation, particularly in the setting of ongoing allergen exposure.? ? 2) Function of D6 in allergic pulmonary inflammation.? The chemokine receptor, D6, binds multiple chemokines of the beta subfamily, but does not signal in response to these chemokines. We used D6-deficient mice to study the function of this receptor in allergic pulmonary inflammation. Unexpectedly, sera of allergen-sensitized D6-deficient mice had markedly elevated IgE compared to similarly sensitized, genetically-matched C57BL/6 mice. These differences were seen regardless of the procedure used to sensitize mice, and remained significant following challenge with aerosolized allergen. The ability of D6 to affect chemokine availability in the lung depended on the chemokine concentration. Chemokines present at either very low or very high concentrations were unaffected by D6, but when present at moderate levels, CCL17 and CCL22 were significantly increased in D6-deficient mice compared to C57BL/6 mice. Analysis of pulmonary leukocytes revealed that challenged D6-deficient mice also had more dendritic cells, T cells and eosinophils in the lung parenchyma and more eosinophils in the airway. Surprisingly, despite the increased levels of inflammation seen in the D6-deficient mice, they had reduced airway hyperreactivity compared to similarly-challenged wild type mice. Together, these findings define a novel role for D6 in humoral immunity and reveal conditions under which D6 impacts chemokine availability in vivo. The similar chemokine binding profiles of murine and human D6 suggest that this receptor might also affect humoral and allergic responses in humans.? ? ? 3) Function of CCR6 in allergic pulmonary inflammation.? Dendritic cells (DCs) are required during the effector phase of immune responses as well as during the sensitization phase. Here, we used gene targeted mice to determine the requirement of individual chemokine receptors for recruiting functional DCs to allergen-challenged lungs. When challenged once with aerosolized allergen, sensitized CCR6-deficient mice responded similarly to wild type mice, as measured by eosinophilic accumulation in the airway and production of Th2 cytokines. However, when challenged repeatedly with allergen, CCR6-deficient mice had dramatically diminished responses compared to similarly challenged wild type mice. Prior exposure to aerosolized endotoxin also abrogated allergic responses in lungs of CCR6-deficient mice, but not wild type mice, and suggested that CCR6 is required to sustain allergic responses in the inflamed lung. Unchallenged wild type and CCR6-deficient mice had similar numbers of pulmonary DCs. However, exposure to aerosolized allergen or endotoxin increased the number of DCs in wild type mice, whereas these treatments reduced the number of DCs in CCR6-deficient mice. Allergic responses in previously-challenged CCR6-deficient mice could be restored either by adoptive transfer of allergen-loaded, bone marrow-derived DCs into the airway or by allowing the animals to recover for 12 days before exposing them to subsequent aerosol challenges. Taken together, these findings demonstrate that allergic immune responses are sustained in the lung by rapid, CCR6-dependent recruitment of DC precursors.
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