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*
Departments of Medicine and Biochemistry, The Lawson Research Institute, St. Joseph’s Health Centre, The University of Western Ontario, London, Ontario, Canada;
Department of Pathology, Barnes Jewish Hospital of St. Louis, Washington University Medical Center, St. Louis, MO 63110 and
Department of Cell Biology, Duke University, Durham, NC 27710
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Pulmonary surfactant is composed of various phospholipids and neutral lipids as well as four surfactant-associated proteins designated surfactant-associated protein A (SP-A)3, surfactant-associated protein B, surfactant-associated protein C, and surfactant-associated protein D (SP-D) (8). Surfactant-associated proteins B and C are highly hydrophobic and directly interact with surfactant lipids to reduce surface tension and enhance spreading of the lipid monolayer over the airspace (8). Although SP-A and SP-D also interact with surfactant lipids, they are hydrophilic and appear to have more diverse biologic functions. SP-A is the most abundant of the surfactant-associated proteins. It specifically binds to the dipalmitoylphosphatidylcholine (9) and is usually isolated from the lung in association with surfactant lipid (9, 10). SP-D can also bind to specific surfactant lipids (phosphatidylinositol and glucosylceramide), but the majority of protein exists in the aqueous phase of the lung-lining material (9, 10).
SP-D belongs to a family of glycoproteins, referred to as collectins, that are comprised of a collagen-like region and a C-type lectin carbohydrate-binding domain (11, 12). Other collectins include mannose-binding protein, conglutinin, and SP-A (12, 13). The collectins vary in carbohydrate binding specificity and oligomeric structure (11, 12). However, most have been shown to interact with microorganisms and influence leukocyte function (12, 14, 15, 16, 17, 18, 19, 20, 21). Although the primary function of SP-D within the airspace is still unknown, recent studies suggest that this molecule also plays an active role in host defense in part through opsonization of microorganisms and through more direct interactions with host defense cells (14, 15, 16, 22).
SP-D is assembled as a cruciform oligomeric structure of four trimeric subunits and contains a single site of N-linked glycosylation within the collagen domain (23). Oligomerization of trimeric subunits appears to be required for various aggregation-dependent host defense activities involving bacteria, fungi, and viruses (14, 15, 16). However, other activities such as stimulated neutrophil or monocyte chemotaxis or influenza A virus hemagglutination inhibition appear to be mediated by binding of single, trimeric carbohydrate recognition domains (22).
The objective of the current study was to examine the effects of SP-D on cultures of PBMCs and determine whether SP-D might contribute to the suppression of stimulated T cell proliferation by airspace-lining material. Preliminary experiments indicated that purified SP-D dodecamers could inhibit PHA- (1 µg/ml) stimulated T cell proliferation in vitro, as described previously for bovine (24), human, and both mutant and wild-type (wt) recombinant rat SP-A (rrSP-A) (25). Therefore, we performed studies to further characterize this inhibitory activity. In particular, we examined the effects of rrSP-D and selected structural mutants of SP-D on T cell proliferation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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29–37
rrSP-D was stably expressed in Chinese hamster ovary K1 cells
using a glutamine synthetase selection system (23). The wt protein is
efficiently secreted as a fully assembled dodecamer and shows a profile
of posttranslational glycosylation and hydroxylation identical with
natural SP-D (23). rrSP-D is functional as a lectin and appears
indistinguishable from natural rat SP-D in its interactions with
various microorganisms and leukocytes (25). Production of selected
structural mutants of rrSP-D was accomplished by overlap-extension
mutagenesis of a full-length rat SP-D cDNA as described previously (23, 26). In each case, a restriction fragment containing the mutant SP-D
sequences was subcloned into the corresponding site of rrSP-D/pGEM-3Z.
These mutant rat SP-D cDNAs were expressed in Chinese hamster ovary K1
cells as described for the wt protein. rrSP-Dser15/20 is characterized
by the combined substitution of Ser for Cys 15 and Cys 20 of the mature
protein (26). Because these residues are required for intersubunit
cross-linking and the covalent stabilization of dodecamers, the mutant
can only form trimers (one arm of the cruciform structure of wt SP-D)
and is defective in various aggregation-dependent activities.
rrSP-Dala72 is characterized by the substitution of Ala for Ser
72, resulting in a loss of the consensus for N-linked
glycosylation (NGS) at Asn 70 (12). rrSP-D29–37 lacks
a conserved hydrophilic sequence (DGRDGR) near the
amino-terminal end of the collagen domain. The secreted protein binds
to maltosyl agarose, migrates slightly faster on SDS-PAGE than wt SP-D,
and elutes at the expected position of dodecamers by gel filtration
chromatography (data not shown).
Cell isolation and culture
Lymphocytes and monocytes were obtained from the peripheral blood of healthy volunteers by buoyant density centrifugation using Lymphoprep resolving medium (Nycomed, Oslo, Norway). PBMCs were then washed three times in cold tissue-culture media, RPMI 1640 (Life Technologies, Burlington, Canada) containing penicillin (100 µg/ml, Life Technologies), streptomycin (100 µg/ml, Life Technologies), amphotericin-B (2.5 µg/ml, Life Technologies), 2-ME (5.5 x 105 M, Life Technologies), and gentamicin (0.1 µg/ml, Life Technologies). Before culture, tissue-culture media was supplemented with 10% (v/v) newborn calf serum (Life Technologies). Cells were cultured at a concentration of 1 x 105 cells/well, 100 µl/well in flat-bottom 96-well sterile plates (Corning Glass, Corning, NY).
T cell proliferation assays
Three different T cell mitogens were used for these experiments: 1) PHA (1 µg/ml), 2) Con A (2 µg/ml) (Sigma, St. Louis, MO), and 3) anti-CD3 (UCHT-1, 50 ng/ml, ID Labs, London, Canada). Varying amounts of human complement component C1q (hC1q) (Sigma), rrSP-D and SP-D mutants, human rIL-2 (rhIL-2) (ID Labs or R&D Systems, Minneapolis, MN), and maltose (Sigma) were added to the stimulated lymphocytes in various concentrations. Maltose was combined with cells at 0.1 and 0.5 mg/ml. A 5-aa, DGR-containing peptide (Ser-Asp-Gly-Arg-Gly, Sigma) was also compared in proliferation assays with an RGS-containing sham peptide (Gly-Arg-Gly-Ser-Pro, Life Technologies) at various concentrations. Cultures were incubated at 37°C with 5% CO2 in a humidified atmosphere for 72 h. At the 60-h timepoint, 1 µCi/well of [3H]thymidine was added (specific activity of 6.7 Ci/mmol, Amersham International, Oakville, Canada). Cells were subsequently harvested using a semiautomated Skatron cell harvester (Lier, Norway), the filter papers were dried, and the amount of [3H]thymidine incorporated into DNA was measured via liquid scintillation spectrophotometry. Data are expressed as the mean ± SE of the mean percentage of [3H]thymidine incorporation compared with cultures treated with mitogen only.
Assay for IL-2
PBMCs were isolated as described previously and cultured in 96-well flat-bottom wells at a density of 2 x 105 cells/well in 250 µl of tissue-culture media. Cells were cultured with or without 1 µg/ml of PHA and a single concentration of rrSP-D (6.25 µg/ml). Cultures were harvested under aseptic conditions, and cells were removed by centrifugation of supernatants in an Eppendorf microcentrifuge (Hamburg, Germany) at 14,000 rpm for 1 min. Supernatants were stored at -70°C until analysis; they were analyzed using a human IL-2 ELISA (R&D systems) under conditions specified by the manufacturer. Undiluted supernatants were used for the assay. Each experimental condition was performed in duplicate.
Statistics
All results shown are expressed as means of a minimum of three separate experiments. Statistical significance between experimental groups was determined first by a one-way ANOVA followed by a comparison of groups using the Student Newman-Keuls test. p values of <0.05 were considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, A and B). The
effects were dose-dependent and statistically significant. By contrast,
hC1q, a collagenous protein that shows many structural similarities to
the collectins, had no effect on [3H]thymidine
incorporation in these assays. To help exclude the possibility that the
effects were secondary to interactions of the lectins with the
oligosaccharide moieties of SP-D, a third T cell mitogen, anti-CD3
(mAb UCHT-1), was also tested (Fig. 1C). Specifically,
rrSP-D inhibited anti-CD3-induced T lymphocyte proliferation in a
dose-dependent fashion. hC1q again lacked the ability to attenuate T
cell proliferation at any of the concentrations tested.
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, coculture
with rrSP-D reduced the quantity of IL-2 detected in culture
supernatants by approximately threefold compared with stimulated cells
alone. Furthermore, the addition of rhIL-2 returned the rate of
proliferation to 160% of cultures stimulated with PHA alone (Fig. 3).
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, the presence of maltose at 0.1 and 0.5
mg/ml, concentrations which are known to block high-affinity
interactions with many multivalent particulate ligands, had no effect
on the inhibitory activity of rrSP-D.
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, rrSP-Dala72 dodecamers showed
comparable inhibitory activity with the wt protein. Although
rrSP-Dser15/20 was fourfold more potent than SP-D dodecamers on a
weight basis, its inhibitory activity was approximately equivalent to
that of rrSP-D on a molar basis (i.e., four trimeric subunits per
dodecamer).
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Mutagenesis of an RGD sequence in recombinant SP-A was found previously
to decrease the inhibitory effects of SP-A on lectin-stimulated T cell
proliferation (24). Comparison of SP-D sequence from rat (27), bovine
(14), human (28), and mouse (29) cDNA libraries has revealed no
evidence of an RGD sequence. However, there is a conserved, repeated,
inverted RGD sequence at positions 31 to 36 in the collagen-like region
(Fig. 6). Therefore, we tested whether it
was possible for a DGR-containing peptide to inhibit T cell
proliferation. As shown in Figure 7, a
DGR peptide (SDGRG) inhibited anti-CD3- (50 ng/ml) stimulated PBMC
proliferation at concentrations as low as 50 µg/ml. A control
pentapeptide (GRGSP) showed no inhibitory effect at even the highest
concentration. Furthermore, the SDGRG peptide (100 µg/ml) inhibited
PHA-stimulated PBMC proliferation to 83.6% (±4.5%) of the
proliferation observed in cultures treated with PHA alone. Addition of
hIL-2 significantly decreased the inhibitory effect of the peptide
(164.5% ± 27.4%).
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29–37). Table I shows the results of proliferation
assays using PHA- (1 µg/ml) stimulated PBMCs and a 6.25 µg/ml dose
of the SP-D mutants rrSP-Dser15/20, rrSP-Dala72, and rat SP-D29–37.
Interestingly, the mutant showed potent inhibition of T cell
proliferation at 6.25 µg/ml, similar to wt SP-D.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The opsonic activities of the collectins have been extensively
investigated. However, these proteins may have other important host
defense functions. For example mannose-binding protein can activate the
alternative complement pathway (17). In this regard, the present study
has shown that SP-D has an inhibitory effect on the T cell
proliferation generated by three separate T cell mitogens at
concentrations less than what has been estimated to be present in the
total lung-lining material of rats (
11.3 µg) (10). These effects
are associated with a decrease in IL-2 production and are significantly
reversed by rIL-2. By contrast, the functionally distinct control
collagenous protein hC1q did not inhibit proliferation, suggesting that
the collagenous structure per se is not responsible for the inhibition
of T cell proliferation. These observations are entirely consistent
with a study published by Malhotra et al. showing that SP-D and C1q do
not share a common receptor on the surface of alveolar macrophages
(32).
In some respects, our results with regard to the inhibitory effect of SP-D on IL-2-dependent T cell proliferation are similar to our previous findings using bovine SP-A (24, 25), suggesting that SP-A and SP-D may share a common mechanism for inhibiting T cell proliferation during early events requiring T cell/accessory cell interactions. On the other hand, bovine SP-A was shown to suppress PHA and anti-CD3 but not Con A-stimulated T cell proliferation. This difference could reflect fundamental differences in the mechanism of interaction of SP-A and SP-D with Con A or other possible effects of Con A. For example, the oligosaccharide chains of SP-A are in the carboxyl terminal domain near the sugar-binding sites of SP-A, whereas the N-linked sugars of SP-D are located near the amino terminus. Studies are in progress to examine potential interactions between the collectins and plant lectins. In any case, our results with anti-CD3 exclude the possibility that either SP-A or SP-D are mediating their effects through interactions with the plant lectin, thereby inhibiting lectin binding to the PBMCs and the resulting T cell proliferation. Experiments will also be required to determine whether SP-D (or SP-A) act directly on T cells, accessory cells, or both in vitro and whether this inhibition is the result of SP-D inducing the production of antiinflammatory mediators such as PGE2.
There are several observations that argue against T cell death or apoptosis as the mechanism by which SP-D inhibits T cell proliferation. First, no observable loss in cell viability was associated with SP-D treatment. Second, addition of rIL-2 in the presence of mitogen and SP-D increased T cell proliferation. This observation contradicts an apoptosis-driven mechanism of inhibition. Lenardo had shown previously that Ag-driven T cell death is actually increased when higher concentrations of IL-2 are present before and during the stimulation of T cells via the TCR (33). However, we observed that addition of 100 U/ml of rhIL-2 increased T cell proliferation in the presence of SP-D. The decreased IL-2 detected in SP-D-treated cultures and a lack of coincidental decline in cell viability also argues against passive T cell death via IL-2 removal (34).
In summary, this study has demonstrated that SP-D can inhibit anti-CD3-, PHA-, and Con A-stimulated lymphocyte proliferation, as well as PHA-stimulated IL-2 secretion. Interference with an IL-2-dependent pathway is indicated by the counteracting effect of added rIL-2. The inhibitory activity of SP-D is not mediated by its lectin activity, by multimerization of the trimeric subunits, or by cellular interactions with the N-linked oligosaccharide at Asn 70 or with the repeated DGR sequence at positions 29 to 37. SP-D-mediated suppression also does not simply reflect interactions with a generic collagen domain, since hC1q showed no inhibitory capacity. Our data suggest that cellular recognition of a DGR sequence may be one mechanism by which T cell proliferation can be inhibited. Nevertheless, this does not appear to be the dominant mechanism of interaction of SP-D. Approximately 1000-fold greater molar concentrations of the peptide were required than of SP-D. Furthermore, we observed no significant inhibition with similarly high concentrations of a synthetic 13-aa SP-D peptide containing this sequence, and inhibition was not blocked with a polyclonal Ab to this sequence (data not shown).
We hypothesize that SP-D significantly contributes to the inhibition of in vivo T cell proliferation, and that this effect contributes to the overall hyporesponsive state of leukocytes located in the lung. The data presented in this study and others may suggest that SP-D represents another means of maintaining a balance between the necessary removal of inhaled insults and protection against collateral immune-mediated damage (11, 17).
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Paul J. Borron, Department of Cell Biology, Box 3709, Duke University Medical Center, Durham, NC 27710. E-mail address:
3 Abbreviations used in this paper: SP-A, surfactant-associated protein A; SP-D, surfactant-associated protein D; wt, wild-type; rrSP-D, recombinant rat SP-D; rhIL-2, human rIL-2; hC1q, human complement component C1q.
Received for publication September 17, 1997. Accepted for publication June 26, 1998.
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ß T lymphocytes for apoptosis. Nature 353:858.[Medline]
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M. van Eijk, H. P. Haagsman, T. Skinner, A. Archibold, K. B. M. Reid, and P. R. Lawson Porcine Lung Surfactant Protein D: Complementary DNA Cloning, Chromosomal Localization, and Tissue Distribution J. Immunol., February 1, 2000; 164(3): 1442 - 1450. [Abstract] [Full Text] [PDF]
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 U. Holmskov, J. Mollenhauer, J. Madsen, L. Vitved, J. Gronlund, I. Tornoe, A. Kliem, K. B. M. Reid, A. Poustka, and K. Skjodt Cloning of gp-340, a putative opsonin receptor for lung surfactant protein D PNAS, September 14, 1999; 96(19): 10794 - 10799. [Abstract] [Full Text] [PDF]
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 L. Zhang, M. Ikegami, E. C. Crouch, T. R. Korfhagen, and J. A. Whitsett Activity of Pulmonary Surfactant Protein-D (SP-D) in Vivo Is Dependent on Oligomeric Structure J. Biol. Chem., May 25, 2001; 276(22): 19214 - 19219. [Abstract] [Full Text] [PDF]
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B. C. Trask, M. J. Malone, E. H. Lum, H. G. Welgus, E. C. Crouch, and S. D. Shapiro Induction of Macrophage Matrix Metalloproteinase Biosynthesis by Surfactant Protein D J. Biol. Chem., October 5, 2001; 276(41): 37846 - 37852. [Abstract] [Full Text] [PDF]
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