Linkages of innate and adaptive immunity: Differential regulation of dendritic cell functions by surfactant proteins A and D

Surfactant proteins (SP) A and D are components of pulmonary surfactant that have known roles in innate immunity to regulate pathogen clearance and lung inflammation. A role for SP-A and SP-D in innate immunity was originally postulated based on their structural similarity to a family of proteins termed collectins that function as soluble pattern recognition molecules to opsonize pathogens for phagocytosis by immune cells. The lung collectins modulate a variety of immune functions including phagocytosis, cytokine production, chemotaxis, and T cell proliferation, however, little is known about regulation of adaptive immunity by SP-A and SP-D. Dendritic cells (DCs) are the most potent antigen-presenting cell with the unique capacity to activate naïve T cells and initiate adaptive immunity. The goal of this dissertation was to test the hypothesis that the surfactant proteins functionally interact with DCs to modify adaptive immune responses. Using mouse bone marrow-derived DCs (BMDCs), the data show that SP-A and SP-D bind to immature BMDCs, but that SP-D binding is reduced on BMDCs matured with either LIPS or GM-CSF. Although both lung collectins enhance the association of a broad range of pathogens with immature BMDCs, only SP-D enhances the antigen presentation of Escherichia coli to antigen-specific MHC class II T cell hybridomas. The enhancement of antigen presentation by SP-D is not shared by other collectin-like proteins tested, is specific to the MHC-II presentation pathway, and is partly dependent on bacterial aggregation. We hypothesized that the specific enhancement of antigen presentation by SP-D may be due to effects on the maturation of BMDCs. Incubation of immature BMDCs for 24 hours with SP-A inhibits basal- and LPS-mediated expression of MHC class II and CD86 and LPS-mediated stimulation of cytokines as assessed by RNAase protection assay. Stimulation of immature DCs by SP-A also inhibits the allostimulation of T cells, enhances dextran endocytosis, and alters DC chemotaxis towards Rantes (CCR5) and SLC (CCR7). The effects on DC phenotype and function are similar for the structurally homologous C1q, but not for SP-D. These studies demonstrate that SP-A and SP-D participate in adaptive immunity by differentially modulating important immune functions of DCs.