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Abstract |
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Abstract
Introduction
Materials & Methods
Results
Discussion
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Alveolar macrophages (AM) from sarcoid patients have been shown to be good antigen presenting cells (APC) unlike normal AM which are usually ineffective. We demonstrate in ten consecutive sarcoid patients that most of their AM, unlike normal AM, do coexpress high levels of CD86, CD40, and CD30L, all known to be important for T-cell activation. CD80 is also slightly more expressed on sarcoid AM than on normal AM, but is detected on only 26 ± 6% (mean ± SEM) of sarcoid AM. A good correlation is present between the percentage of sarcoid AM expressing CD86 and CD40 or CD86 and CD30L. However, no correlation is found between the percentage of CD80 and CD86 positive AM in these same patients. Blocking antibodies against CD86 were able to reduce by more than 80% allogeneic T-cell proliferation induced by the AM of sarcoid patients. This study provides evidence that AM can, in pathologic states such as sarcoidosis, express functional costimulatory molecules for T-cell activation such as CD86, thought to be rather specific for more professional APC such as dendritic cells.
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Introduction |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Human alveolar macrophages (AM), resident phagocytic
cells in the lung that derive from peripheral blood monocytes (1) are usually ineffective in presenting antigens to
T cells (2). Among various mechanisms suggested to explain this poor function as antigen presenting cells (APC),
it has been shown that AM have a defective expression
of B7 costimulatory cell surface molecules (3). The same
authors showed that even when AM were activated with interferon-
(IFN-), they failed to express CD80 or
CD86 antigens (3). CD80 or CD86 normally ligate CD28
on T cells to provide costimulatory signals required for the
activation of T cells (4).
In contrast to AM from normal lungs, AM from sarcoid patients have been shown to have an enhanced capacity to mediate antigen-induced T-lymphocyte proliferation (5, 6). In addition, numerous data suggest that AM in sarcoidosis are in an immunologically activated state. Thus, while phenotypic studies have not shown an increased density of class II major histocompatibility molecules on sarcoid AM, they show an increased expression of the accessory molecules CD11 and CD18 known to play a role in T-cell activation (5, 7). Sarcoid AM also release proinflammatory cytokines such as tumor necrosis factor-alpha, interleukin (IL)-6 and IL-1 beta (8, 9), that may stimulate T-cell proliferation.
The mechanisms for the enhanced antigen presentation
in sarcoid lung have, however, remained unclear and important ligands in the interaction between APC and T cells
remain to be explored. B7 molecules, either CD80 or
CD86, have been shown to be able to transmit essential
signals for T lymphocytes through the ligand CD28 or
CTLA-4. CD80 and CD86 are expressed by powerful APC
such as human blood dendritic cells (10). We asked
whether sarcoid AM express these molecules to explain
why they are effective APC. Among other candidates to
explain the APC function of sarcoid AM is CD40. CD40
present on APC is known to interact with its ligand
(CD40L) expressed on activated T cells. This interaction is
not only important to induce anti-tumoral immunity but
also for cell-mediated immunity in general (11). Activated
T cells expressing high levels of CD40L could also trigger
CD40 present on dendritic cells to induce IL-12 production and enhanced CD80 and CD86 expression on the
APC (12, 13). T cells expressing CD40L have also been
shown to induce the release of key proinflammatory cytokines such as tumor necrosis factor-
, IL-1
, IL-6 and
IL-8 from APC (14). Thus the CD40 present on the APC
can provide signals to T cells through their CD40L, and
vice versa T cells can activate the APC in their functions,
thus amplifying immune processes.
CD30L is another molecule present on APC which could be important for APC-T-cell interaction. The precise role of CD30L on the APC remains to be established. However, several reports have shown that CD30 expressed on T cells is a member of the tumor necrosis factor/nerve growth factor receptor family. CD30 could be preferentially expressed on CD4 and CD8 T-cell clones that produce T helper 2-type cytokines (15). Thus APC expressing CD30L could favor Th2 cytokines release.
We show that a high percentage of sarcoid AM express high levels of important accessory molecules, namely CD86, CD40, and CD30L. CD80 is present only on a subset of AM obtained from sarcoid patients and with a lower level of expression than CD86, although they are both from the B7 family. The expression of CD40 and CD30L, individually, correlates with the expression of CD86, whereas the expression of CD86 and CD80 shows little correlation.
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Materials and Methods |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Reagents
Control mouse IgG, anti-CD14 (clone IOM2) and anti-CD40 (clone MAB89) were from Immunotech (Marseille, France). Anti-B7.1 monoclonal antibody (mAb) (clone L 307.4) was purchased from Becton Dickinson (Mountain View, CA), anti-B7.2 mAb (clone IT2.2) was from Pharmingen (San Diego, CA). Anti-CD30L mAb was from Genzyme (Cambridge, MA). Anti-HLA-DR mAb was from DAKO (Glostrup, Denmark). Fluorescein (DTAF)-conjugated F(ab')2 fragment goat anti-mouse IgG was provided by Immunotech.
Culture Medium
RPMI 1640 medium supplemented with 10% heat-inactivated fetal calf serum (FCS), 2 mM L-glutamine, 100 U/ml penicillin, and 100 µg/ml streptomycin was used (Gibco, Paisley, Scotland).
Study Populations
Ten consecutive patients with sarcoidosis were analyzed in our laboratory (three women and seven men, average age 35.8 ± 9.6 yr). In 8 of 10 cases, the diagnosis was made by biopsy obtained either from the lungs or from lymph nodes, and showed epitheloid cell granulomas with no evidence for pathogens known to cause granulomatous diseases. In 2 cases, the diagnosis was made by the presence of bilateral hilar adenopathies with bronchoalveolar lavage (BAL) lymphocytosis and a high CD4/CD8 ratio. Each patient underwent BAL analysis. The number of cells was 55 ± 15 × 104 cells/ml (mean ± SEM) with 51 ± 5% macrophages; 45 ± 5% lymphocytes; 2.1 ± 0.4% neutrophils, and 0.8 ± 0.6% eosinophils. The ratio of CD4/ CD8 T lymphocytes in BAL was of 6 ± 1.7 (mean ± SEM) as measured by flow cytometry using an EPICS V flow cytometer (Coulter Immunology, Hialeah, FL). Aside from the BAL analysis, the assessment of disease stage was done with chest radiographs. A stage I, II, or III disease on chest X-ray was found in 3, 4, and 3 cases, respectively. Systemic corticosteroids were administered at the time of BAL in 3 cases.
Preparation of Cell Suspension
After local anesthesia, BAL was performed by injecting a total of 150-200 ml of saline solution via fiberoptic bronchoscopy in 50-ml aliquots, followed by immediate vacuum aspiration after each aliquot. Cells recovered from the BAL were washed three times with Hank's balanced salt solution without calcium and magnesium (HBSS; Gibco) and resuspended in RPMI 1640 complete medium at the concentration of 1 × 106 cells/ml.
Control Population
Human alveolar macrophages obtained by BAL of 7 normal surgical specimens next to pulmonary carcinomas were used as control (two women and five men, average age 65.1 ± 10.2 yr). As previously described, segments or lobes were lavaged at room temperature with 250-500 ml of sterile 0.9% NaCl using a 50-ml syringe introduced in the major bronchial airways (16). The cells obtained were > 85% macrophages and < 2% neutrophils as determined by differential counting of Wright-stained cytocentrifuge preparations. Alveolar macrophages were centrifuged, washed 3 times with HBSS (Gibco) and resuspended in RPMI 1640 complete medium at the concentration of 1 × 106 cells/ml.
Flow Cytometric Analysis
The expression of CD14, B7.1 (CD80), B7.2 (CD86), CD40, and CD30L on BAL macrophages from sarcoid patients was compared with alveolar macrophages obtained from control population. BAL cells were stained by incubating the cells with the different mAbs for 45 min at 4°C. To reveal the surface markers, fluorescein-conjugated (Fab')2 fragments of goat anti-mouse IgG were used. BAL macrophages were gated in flow cytometry analysis using two different parameters: size (forward scatter) and complexity (side scatter) as shown in Figure 1. The purity of AM was assessed by May-Grünwald staining and by the expression of HLA-DR antigens present in greater than 90% of this population. Five thousand cells bearing the typical size and complexity were scored. As BAL exhibited relatively homogeneous fluorescence intensity for the different markers, but diverged in their autofluorescent background, the data are presented mostly as percent of positive cells for CD14, CD80, CD86, CD40, and CD30L. The gates to define the number of positive cells were chosen in order to have < 1% positive cells with the control isotype matched mAb. Results are expressed in mean ± SEM. When data are also given in mean fluorescence intensity, it is mentioned if it is done after subtraction of the nonspecific fluorescence obtained with the control irrelevant antibody and the naturally occurring autofluorescence of AM.
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Mixed Leukocyte Reactions
BAL from sarcoid patients were irradiated with a cesium source (3,000 rads). BAL macrophages (25 × 103) were cocultured with purified T lymphocytes (15 × 104) in 200 µl of RPMI 1640 complete medium in 96-well culture plates (Costar, Cambridge, MA) at 37°C. T lymphocytes were purified from buffy coats of healthy donors. Briefly, mononuclear cells were isolated from buffy coats by centrifugation on Ficoll-Paque (Pharmacia, Uppsala, Sweden). Monocytes were removed by 1 h adherence on plastic (Costar, Cambridge, MA). To isolate T cells, non-adherent mononuclear cells were passed twice through a nylon wool column. To assess the function of CD80 and CD86 molecules on BAL cells from sarcoid patients, anti-CD80 mAb and anti-CD86 mAb (10 µg/ml) were added to the MLR between BAL macrophages and T cells. After 5 days of cocultures, cells were pulsed with 0.5 µCi [3H]thymidine (Amersham, UK) 18 h before harvest. The cells were aspirated onto filter paper, and the radioactivity was analyzed in a liquid scintillation counter and data given in cpm.
Statistics
Statistics were performed using the program Statview 4.05 (Abacus Concepts, Berkeley, CA). The Mann-Whitney rank sum test was used to compare percent of cells expressing various markers among the sarcoid AM as compared with control subjects. Simple regression analysis was used to find out if a correlation was present between the percent of cells expressing the various markers in the sarcoid AM.
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Results |
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Materials & Methods
Results
Discussion
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Phenotypic Analysis of Sarcoid and Control AM
The percentage of AM obtained by BAL from sarcoid patients and expressing the costimulatory molecules for AM-T cells signaling was analyzed. A representative of the experiments of the various markers analyzed is shown in Figure 2. Besides HLA-DR, the marker expressed with highest intensity on more than 95% of the AM, it is apparent that CD86, CD40, and CD30L are also detected on a majority of sarcoid AM.
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In contrast to HLA-DR or CD86, CD80 was present at rather low intensity (Figure 2). After subtraction of the fluorescence obtained with the control antibody, the fluorescence of CD80 was of 9.1 ± 1.6 arbitrary units (mean ± SEM) on the sarcoid AM of all ten patients studied. In addition, CD80 was present on only 26.9 ± 5.7% of sarcoid AM (mean ± SEM). This percentage was, however, higher than in the control AM as only 3.5 ± 0.9% of these cells expressed CD80 (P < 0.01 by Mann-Whitney rank sum test; Figure 3).
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CD86 expression was strong on sarcoid AM (Figure 2). The CD86 expression in arbitrary units was of 34.9 ± 9.3 after subtraction of the fluorescence obtained with the control antibody in all ten patients, while its intensity was of 8.5 ± 3.1 arbitrary units in the control population. The percentage of CD86 positive sarcoid AM was 71.5 ± 9.0%, by contrast only 4.5 ± 1% of control AM expressed CD86 (P < 0.01; Figure 3).
CD40 expression was also very high on sarcoid AM (Figure 2). The mean fluorescence intensity obtained with this marker, after subtraction of the fluorescence from the control antibody, was of 47.6 ± 7.8 arbitrary units. The mean percentage of CD40 positive sarcoid AM reached 78.3 ± 7.9% while it was present on only 3.7 ± 0.9% AM of control subjects (Figure 3). There was a close correlation between the number of AM expressing either CD86 or CD40 in all patients with sarcoidosis (r = 0.85; P < 0.001 by simple regression analysis) (Figure 4). Meanwhile, no correlation was found between CD86 and CD80 (r = 0.06; P = 0.4) or between CD86 and CD14 (r = 0.38; P = 0.06).
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CD30L was expressed by an average of 56 ± 7.8% of AM in sarcoid patients (Figure 3). CD30L was expressed on the same proportion of AM than CD86 in patients with sarcoidosis. The degree of correlation between CD30L and CD86 was close to the correlation obtained between CD86 and CD40 (r = 0.81; P < 0.001) (Figure 4). The coexpression of these molecules could imply that both are induced by a similar stimuli. Alternatively, when AM interact with T cells through CD40 and CD40L for instance, AM could be driven to express higher levels of other molecules such as CD86 or CD30L. Such a succession of events has been described for dendritic cells (13).
Functional Analysis of Sarcoid AM in Alloreactions
Addition of mAb directed against CD86 to allogeneic MLR induced with AM from sarcoid patients did markedly reduce T-cell proliferation (Figure 5). The addition of anti-CD80 mAb had low or no inhibitory effect as compared with irrelevant IgG. No effect was observed when alloreaction was conducted with the antibodies against CD40 and CD30L used in this study (data not shown). These results at least demonstrate that CD86 was functional on sarcoid AM.
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Discussion |
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Abstract
Introduction
Materials & Methods
Results
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This study provides evidence that not only dendritic cells but also AM can in some pathologic states such as sarcoidosis express the accessory molecules CD80, CD86, CD40, and CD30L. In sarcoidosis, there is a good correlation between the expression of CD86, CD40, and CD30L, while no correlation between CD80 and CD86 is found. The expression of these molecules contribute to the good APC function of sarcoid AM described in the past (5, 6), as at least blocking antibodies against CD86 suppressed allogeneic T-cell proliferation induced by these macrophages.
CD80 and CD86 are expressed by human dendritic
cells and are important costimulatory signals for the activation of CD4 and CD8 T lymphocytes (10). Monocytes
have been shown to be able to express CD80 or CD86 only
after prolonged stimulation by IL-4 and GM-CSF (17) or
by IFN- (3). However, it has been impossible to induce
CD80 on AM and CD86 only to a low extent in the same conditions (3). Our results provide evidence that AM in
sarcoidosis can nevertheless express CD86 and efficiently
activate T cells. Proliferation induced by allogeneic sarcoid AM is shown to be markedly inhibited by blocking
antibodies against CD86, demonstrating its importance for
the APC function of these cells. The conditions that lead
to CD86 expression in sarcoidosis are unknown at present. Unidentified microbial constituents have been reported to
induce B7 on murine macrophages (18). Unknown pathogen could similarly induce B7 on sarcoid AM. Alternatively, it is possible that freshly attracted monocytes could
be induced to express these markers under unknown stimuli and then mature into AM, while the expression of these
markers is preserved.
The fluorescence signal for CD86 was consistently
higher on sarcoid AM than CD80. Along with this, we
found no clear evidence for CD80 function on AM in sarcoidosis. The functional necessity for the two CD28 counterreceptors is presently unknown. In a murine model,
CD80 and CD86 costimulate IL-2 and IFN- production
equivalently, but CD86 has also been described to induce
significantly more IL-4 than CD80 with the greatest difference seen in naive T cells (19). As the pattern of cytokines
produced by activated T cells in this disease is not yet
known (20), the role of the enhanced expression of CD86
on sarcoid AM remains to be established.
CD40 has been shown to be required for antigen-specific T-cell priming in vivo by the use of mice lacking CD40 ligand (20). The mice lacking CD40 ligand have a reduced inflammatory response and a reduced capacity of granuloma formation in a Leishmania model (11). The high expression of CD40 on sarcoid AM is therefore likely of importance. The good correlation between CD86 expression and CD40 could be partially explained by the observation that crosslinking of CD40 markedly increases CD80 and CD86 expression (21). This interaction of APC and T cells through CD40 and CD40L is thought to be one of the early events that could enhance the APC function of either dendritic cells or B cells (13). This would be followed by the increased expression of CD80 and CD86 and secondarily to a more effective triggering of T-cell proliferation and cytokine production. The absence of correlation between CD40 and CD80 contrarily to CD40 and CD86 could suggest however that CD80 and CD86 expression is not always linked.
The fact that antibodies against CD40 molecules did not decrease the MLR could be due to the fact that the sarcoid AM that we used had already been activated through this molecule to express high levels of CD86. We were perhaps too late in our assay in vitro to prevent then the alloreaction by blocking CD40 and CD40L interactions as CD86 was already expressed to a high level. Alternatively, it is possible that the antibodies used against CD40 in our assay were not blocking the appropriate epitope. Additional studies are currently being performed.
CD30 belongs to the tumor necrosis factor receptor super family and does activate T cells (22). Its preferential role in activation of Th2 cytokines remains controversial (23). CD30L on sarcoid AM may also be of importance in the physiopathology of sarcoidosis. This is supported by its coordinated expression with CD86 and CD40.
In conclusion, we have provided evidence that AM can, in pathological states such as sarcoidosis, express high levels of CD86, CD40, and CD30L. The mechanisms leading to the overexpression on AM of such markers and their role in sarcoidosis remain unclear and need to be clarified.
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Footnotes |
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Address correspondence to: Laurent P. Nicod, M.D., Pulmonary Division, University Hospital, 1211 Geneva 14, Switzerland.
(Received in original form September 17, 1996 and in revised form December 3, 1996).
Acknowledgments: The authors thank Dr. K. Hauser for his lecture, Dr. P. Jolliet for his assistance in the statistics analysis of the manuscript, and Mrs. F. Songeon for her technical assistance. This work was done with the support of the FNSRS fund No. 32-40844.94; the Lancardis Foundation and the "Association Vaud-Genève" project No. 19.
Abbreviations AM, alveolar macrophages; APC, antigen presenting cells; BAL, bronchoalveolar lavage; SEM, standard error of the mean.
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| Proc. Am. Thorac. Soc. | Am. J. Respir. Crit. Care Med. |