Department of Pathology, Vanderbilt University, Nashville 37232; and Department of Veterans Affairs, Nashville, Tennessee 37212
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.
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REFERENCES
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FOOTNOTES |
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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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