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, particularly with regard to pulmonary DCs. 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. Two of these projects are summarized as follows:? ? 1) 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. 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, the chemokines 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.? ? ? 2) Function of CCR2 in allergic pulmonary inflammation.? Dendritic cells (DCs) are required for the initiation of immune response to antigens, including airborne antigens. DCs lining the airway take up inhaled antigens and subsequently migrate from there to draining lymph nodes where they present antigen to naive T cells. We used gene targeted mice to determine the requirement of individual chemokine receptors for this migration step. We found that during homeostatic conditions, the chemokine receptor, CCR2, was not required from migration of DCs from the lung to draining lymph nodes. However, during allergic sensitizing conditions conferred by low levels of LPS together with ovalbumin, this receptor was required for this migration step. Moreover, CCR2 was also required for allergic sensitization through the airway. Interestingly, CCR2 was found to be dispensible for sensitization by intraperitoneal injections of ovalbumin complexed with alum. Therefore, the chemokine requirements for DC migration is both tissue- and inflammation-dependent.
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