INVITED COMMENTARY
Pulmonary surfactant protein D: a novel link between innate and adaptive immunity

Virginia L. Shepherd

Department of Pathology, Vanderbilt University, Nashville 37232; and Department of Veterans Affairs, Nashville, Tennessee 37212


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DENDRITIC CELLS (DC) are the sentinels of the immune system, constantly surveying the environment for the presence of foreign invaders (13, 14). In addition, these cells function as a unique link between the innate and adaptive immune system by detecting pathogens and triggering T cell activation (8). DC exist at mucosal surfaces in an immature state. One hallmark of these cells is the high level of expression of pattern recognition receptors such as the mannose receptor and toll-like receptors (6, 16). After pathogen recognition and ingestion mediated by these receptors, DC rapidly mature, resulting in dramatic changes in the phenotype of the DC, including a decrease in endocytic rate, increased expression of costimulatory molecules, release of cytokines, expression of new chemokine receptors that assist in trafficking to T cell areas, and increased surface levels of major histocompatibility complex class II (MHC II) and MHC II-peptide complexes involved in T cell activation (5, 13).

Within the lung, immature DC are located in normal human airway epithelium, the alveolar parenchyma, and nasal mucosa (11). After a challenge, DC move into the airway where lung-specific antigen surveillance mechanisms at the challenge sites may be an integral part of the innate immune response. These mechanisms might involve tissue-specific molecules to signal the adaptive arm of this response of the presence of an incoming foreign particle. A unique class of soluble opsonins or pathogen-binding proteins is found in close proximity to these immature DC, namely the surfactant-associated proteins A (SP-A) and D (SP-D) (2, 19). As suggested in the study by Brinker et al. (Ref. 1a), the article on which this paper focuses, these proteins might represent a link between the innate and adaptive arms of the immune system. SP-A and SP-D are members of the calcium-dependent lectin (collectin) family (18). Both collectins bind to a variety of microorganisms and modulate the function of immune cells including macrophages and T cells (2, 19). A number of both in vitro and in vivo studies have underscored the importance of both of these collectins in clearance of microorganisms from the lung (2, 9). SP-A is produced by type II cells in the lung and is localized almost exclusively to the alveolus. SP-D is much more widely distributed. It is synthesized and secreted by alveolar and bronchiolar epithelial cells but also expressed in the mucosa of the gastrointestinal and genitourinary tracts (10). This differing distribution of the two proteins suggests the possibility that they play distinct roles in pulmonary defense.

The findings presented by Brinker et al. (1a) suggest a novel role for SP-D in linking pathogen recognition and uptake to processing and presentation to T cells. Specifically, they have demonstrated that SP-D binds to immature, but not mature, DC. In addition, although previous studies have shown that SP-D can bind to Escherichia coli and enhance its uptake by macrophages, this is the first report showing that SP-D enhances E. coli entry into DC. To demonstrate that this enhanced bacterial uptake leads to presentation to and activation of T cells, the authors used a model system consisting of bone marrow-derived DC, E. coli expressing a specific ovalbumin peptide (Ova), and Ova-restricted T cell hybridomas. When these T cells were cocultured with DC that had been exposed to either SP-D-E. coli complexes or untreated E. coli, SP-D enhanced bacterial uptake, followed by surface expression of the Ova peptide and activation of restricted T cells as evidenced by increased interleukin (IL)-2 production. Furthermore, the authors (1a) suggested that this was specific for SP-D, since other collectins, including SP-A and the serum mannose-binding lectin (MBL), bound E. coli and increased the number of cells with associated bacteria but did not enhance T cell production of IL-2.

At least two possible mechanims are suggested in the study by Brinker et al. (1a) to explain the increased SP-D-mediated pathogen uptake and processing by DC. First, SP-D might redirect E. coli to a more efficient SP-D-specific receptor-mediated delivery system. SP-D regulates a variety of cellular functions, suggesting the existence of a cell surface receptor (9). In addition, SP-D can be found in the phagosomal compartment of macrophages following uptake, again suggesting a receptor-mediated process. Holmskov et al. (4) have reported the cloning of gp340, a putative opsonic receptor for SP-D, but studies have not conclusively demonstrated that this protein is involved in receptor-mediated internalization of SP-D-pathogen complexes. Studies that have examined the role of two other lung lectins in pathogen clearance lend further support to the involvement of a cell surface receptor. The mannose receptor is a cell surface receptor that mediates internalization of pathogens and pathogen-derived molecules by macrophages and immature DC and directs the delivery of these particles to MHC II-containing compartments (7, 12). Recent studies have also identified a specific SP-A receptor on macrophages that binds SP-A-mycobacterial complexes and redirects these complexes to degradative compartments (17). A second possibility raised in the Brinker et al. (1a) study is based on the observation that SP-D, but not SP-A or MBL, increases the number of bacteria per cell. The authors suggest that SP-D binds to and aggregates the bacteria, leading to uptake of the complex and concentration of the bacteria in the antigen presentation pathway.

It has been postulated by other groups that specific molecules at the sites of foreign challenge in tissues might exist to link the innate and adaptive arms of the immune response (11). Colocalization of SP-D and DC in the lung make this lectin an attractive candidate for such a specific link. The observation that SP-D enhances uptake and concentration of E. coli in DC further supports such a role for this SP. The authors also suggest that SP-D might be capable of both initiating an immune response and controlling localized inflammation. In the first scenario, similar to the model recently suggested by Gonzalez-Juarrero and Orme (3), SP-D-pathogen complexes are taken up by immature DC in the lung interstitium. Concomitant with the delivery of pathogen to the intracellular antigen processing compartment, the DC begin a maturation process that results in increased expression of molecules that allow for efficient transport to local lymphoid tissues and increased surface expression of MHC II-peptide complexes for interaction with and activation of T cells. In support of a role in regulation of local inflammation, previous studies from Borron et al. (1) demonstrated that SP-D inhibits the proliferation of T cells stimulated with mitogens. Therefore, while SP-D enhances ingestion of the pathogen, activation of local T cells might be prevented, thus protecting the lung epithelium against damage by inflammatory products. The current studies thus provide an exciting basis for continuing work to elucidate the role(s) that SP-D plays in pulmonary host defense.


    FOOTNOTES

Address for reprint requests and other correspondence: V. L. Shepherd, VA Medical Center, Res Serv 1310 24th Ave. S., Nashville, TN 37212 (E-mail: virginia.l.shepherd{at}vanderbilt.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

10.1152/ajplung.00442.2001


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Am J Physiol Lung Cell Mol Physiol 282(3):L516-L517