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Abstract |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Phenotypic and functional studies are required to understand the immunoregulatory role of mucosal T cells.
Information about T cells in the human upper respiratory tract is limited and conflicting. Therefore, we
phenotyped T cells in nasal mucosa by means of multicolor in situ immunofluorescence. In normal mucosa, most CD3+ intraepithelial lymphocytes (IELs) and lamina propria lymphocytes (LPLs) (> 90%) expressed T-cell receptor (TCR)
/
, and only ~ 5% expressed TCR
/
. Although most IELs in the surface
epithelium were CD8+ (64%), many expressed CD4 (30%) and the CD4 phenotype dominated (55%) only
slightly in the lamina propria. This result was strikingly different from that obtained for comparable compartments in histologically normal jejunal mucosa, where IELs consisted of 83% CD8+ and LPLs of 73%
CD4+ T cells. Nasal CD3+ IELs and LPLs were mainly CD45RO+CD45RA
and usually expressed CD7.
The integrin E7 was, as expected, more common on IELs than on LPLs (78 versus 20%). In conclusion, nasal T cells show several similarities to those of the normal jejunum but some notable differences exist,
especially a relative increase in CD4+ T cells in the epithelium and a decrease in the lamina propria. It
should be explored whether this disparity, together with an increased expression of epithelial adhesion
molecules, might contribute to local immunological overstimulation and partly explain the relatively high
frequency of airway allergy.
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Introduction |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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T cells present in respiratory and gastrointestinal mucosae are believed to play an important role in the regulation of mucosal immune responses to foreign antigens bombarding the mucosal surfaces (1). The local immune systems in both regions are faced with similar problems of discrimination between harmless environmental antigens that should be ignored and infectious microbial antigens that merit rapid and vigorous immune responses. How this balance between immune suppression and hyperresponsiveness is achieved remains poorly understood, but substantial evidence suggests that T cells in the human gut have a unique phenotype that reflects specialized roles for these cells in the mucosa (2).
Whereas peripheral blood T cells consist of a mixture
of naive (CD45RA+) and memory (CD45RO+) subsets,
most intestinal T cells belong to the latter phenotype. This
shift is probably the result of prior activation in mucosa-associated lymphoid tissue, where T cells undergo antigen-driven transition from naive to memory cells. It is believed
that such primed T cells express particular adhesion molecules mediating selective homing to the gut lamina propria
(3). Another unique feature is a striking predominance of
CD8+ (putative cytotoxic/suppressor) T cells in the small
intestinal surface epithelium, contrasting with the large
predominance of the CD4 (helper/inducer) subset in the
lamina propria (more similar to that in peripheral blood).
It has been suggested that the prominent CD8+ intraepithelial lymphocytes (IELs) might have a downregulating immunoregulatory function and therefore contribute to
oral tolerance (4). The compartment-specific retention of
the CD8+ IELs might be explained by their prominent expression of the integrin E7 that binds to E-cadherin on
intestinal epithelial cells (5). Most intestinal lamina propria and intraepithelial T cells express the T-cell receptor
(TCR) / but the TCR/+ subset is relatively enriched
within the epithelium (6). It has been speculated that /
IELs have a special role in the immunological surveillance
of mucosal surfaces (7).
Immunosuppressive mechanisms similar to those in the gut appear to operate in the respiratory tract, particularly controlling IgE responses to inhalant antigens (8). Nevertheless, hypersensitivity against allergens and microbial antigens is much more frequent and persistent in the airways than in the gut (9). To better understand the underlying immunological mechanisms of this disparity, it is necessary to compare T cells of the two regions both phenotypically and functionally.
Studies examining the phenotypes of mucosal T cells in the upper respiratory tract are limited and conflicting. For example, no consensus exists as to whether CD4+ or CD8+ T cells normally predominate in the lamina propria or in the epithelium (10), whereas extensive and comparatively consistent data are available for human intestinal T cells. Further characterization of the resident T-cell population in the upper airway mucosa is therefore needed, both as a basis for evaluation of the immune response in various inflammatory lesions and for comparison of local immunity at different mucosal sites. In this study, we mapped the lamina propria and intraepithelial T-cell phenotypes in histologically normal nasal mucosa as a basis for subsequent disease-related studies. As a reference we used T-cell data from normal human jejunal mucosa obtained by the same two- or three-color immunofluorescence in situ staining method.
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Materials and Methods |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Subjects
Mucosal biopsy specimens from the lower turbinate were obtained from 17 patients. For ethical reasons, this collection of normal mucosa was restricted to patients undergoing nasal surgery (primarily for septum reconstruction) but otherwise healthy. The samples were always obtained from a nostril with macroscopically normal nasal mucosa and free airflow. All samples were histologically examined by two experienced pathologists, and only those deemed to be normal (n = 12) were included in the study (Table 1). The patients had no known allergies (confirmed by a negative skin prick test), had no recent upper respiratory tract illness, and did not receive medication. They were without heavy exposure to industrial or otherwise pollutant air. Patients with previous trauma were not subjected to surgery until at least 6 mo after the accident.
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Histologically normal jejunal mucosa obtained from 10 patients (six men and four women; 13-47 yr old), referred to the hospital for abdominal pain but otherwise found to be healthy, served as reference tissue from the small intestine.
Preparation of Tissue Specimens
The mucosal samples were either fixed in ice-chilled periodate-lysine-0.5% paraformaldehyde for 2 to 6 h or immediately prepared for freezing. The specimens were placed
on a thin slice of carrot for appropriate orientation and
handling, embedded in O.C.T. (Tissue-Tek; Miles Laboratories, Elkhart, IN), snap-frozen in liquid nitrogen, and
stored at 
70°C. Cryosections cut serially at 4 µm were
dried overnight at room temperature, postfixed in acetone
for 10 min, wrapped in aluminum foil, and stored at 20°C
until use.
Two- and Three-Color Immunofluorescence Staining
The methods have been previously detailed (16). For phenotypic examination of CD3+ T cells, each monoclonal antibody (mAb) of the IgG1 subclass (Table 2) directed against a selected lymphocyte surface marker was combined with RIV9 anti-CD3 (IgG3). Likewise, each mAb of the IgG2a subclass (Table ) was combined with SK7 anti-CD3 (IgG1). All these pairs of mAbs were applied for 1 h at room temperature on serial cryosections. Combinations of fluorescein isothiocyanate (FITC)-labeled and biotinylated subclass-specific goat anti-mouse IgG (0.02-0.05 g/liter; Southern Biotechnology, Birmingham, AL) mixed with rabbit antiserum to human cytokeratin (1:100) were next applied for 1.5 h, followed by 7-amino-4-methylcoumarin-3-acetic acid (AMCA)-labeled goat anti-rabbit IgG (0.075 g/liter; Vector Laboratories, Burlingame, CA) in combination Texas Red-streptavidin (0.003 g/liter; GIBCO-BRL, Gaithersburg, MD) for 30 min. The blue (AMCA) cytokeratin staining was included for delineation of epithelial elements.
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To examine whether three different markers were present on the same T cell, RIV9 anti-CD3 was mixed with various pairs of IgG1 and IgG2a mAbs (Table ) and applied for 1 h, followed by a mixture of FITC-labeled goat anti-mouse IgG2a (Southern Biotechnology), biotinylated goat anti-mouse IgG3 (Southern Biotechnology), and rabbit antiserum to CD3 (1:40; Dako, Glostrup, Denmark). This antiserum was included to enhance the staining intensity of CD3. Finally, AMCA-labeled goat anti-rabbit IgG (Vector) and AMCA-labeled streptavidin (1:50; Vector) mixed with indocarbocyanine (Cy-3)-labeled goat anti-mouse IgG1 (0.0015 g/liter; Southern Biotechnology) were applied for 30 min.
For further phenotyping of CD4+CD3 cells, SK3+SK4
(anti-CD4, IgG1) was combined with anti-CD68 (IgG3) or
with anti-HLA-DR (IgG2a) and rabbit antiserum to CD3.
After incubation for 1 h, the corresponding secondary reagents were applied as described above.
To localize definitely CD8+ T cells within glandular epithelium, a mixture of SK1 (anti-CD8, IgG1), RIV9 (anti-CD3, IgG3), and rat anti-laminin (1:800, IgG1; Immunotech, Marseille, France) was applied for 1 h, followed by a mixture of FITC-labeled goat anti-mouse IgG3 (Southern Biotechnology) and biotinylated goat anti-mouse IgG1 (Southern Biotechnology) for 1.5 h. Finally, a mixture of Texas Red-streptavidin and Cy-3-labeled goat anti-rat IgG (1:200; Jackson ImmunoResearch Laboratories, West Grove, PA) was applied for 30 min. The latter reagent delineated the basement membrane with red color.
All antibody reagents were appropriately diluted in isotonic phosphate-buffered saline (PBS), pH 7.5, containing bovine serum albumin (12.5 g/liter). Incubations took place at ambient temperature with intervening 3-min rinses in PBS. Secondary reagents were diluted with human IgG (0.8 g/liter; Kabi Vitrum, Stockholm, Sweden) to block species cross-reactivity. Murine mAbs directed toward keyhole limpet hemocyanin (IgG1 and IgG2a; Becton Dickinson, Mountain View, CA), applied at the usual working concentration, or secondary reagents without application of primary mAbs, provided negative controls.
After the final rinse, the sections were mounted directly (without drying) in buffered polyvinyl alcohol (pH 8.7) that effectively retards fluorescence fading of all fluorochromes during microscopy and section storage.
Microscopy and Photography
The immunostained tissue sections were examined at ×400 magnification in a Leitz DMRDXE microscope equipped with a Ploem-type vertical illuminator and Leitz DMRD camera system (Leitz, Wetzlar, Germany). Synchronous switching of the fluorescence filters facilitated repeated observations of individual cells with regard to Cy-3 or Texas Red emission (red), FITC emission (green), and AMCA emission (blue). In addition, a dual Texas Red-FITC fluorescence filter enabled simultaneous evaluation of double (yellow color) and single (red or green) positive cells. The results were recorded on Ektachrome 800/ 1600 ISO daylight film (Kodak, UK), pushed to 800 ISO.
Histologic and Immunohistochemical Evaluation
All immunostained tissue sections were examined blind by the same investigator (F.L.J.). To determine the density of T cells in nasal mucosa, all CD3+ IELs (median, 994; range, 386-1,969) and CD3+ lamina propria lymphocytes (LPLs) (median, 961; range, 152-2,219) to a stromal depth of 0.25 mm (except those adjacent to glandular structures) were counted by superimposing a luminous grid (7 × 7 lines; 0.25 × 0.25 mm) parallel to the basement membrane. The included area of the surface epithelium (visualized by cytokeratin staining) was determined by measuring the average epithelial height for every grid length and multiplying it by the number of grids examined. To determine the phenotypic T-cell fractions in nasal and jejunal mucosa, more than 100 IELs and more than 200 LPLs were counted for each pair of mAbs applied. IELs and LPLs were in most situations examined in serial sections to optimize the fluorescence intensities.
When the fraction of CD8+ T cells was determined in the glandular epithelium, costaining for laminin was performed to outline distinctly the acinar structures (median number of CD3+ T cells counted in acini, 80; range, 57-163).
Statistical Analyses
The Mann-Whitney test (two tailed) was performed to compare T-cell subsets in nasal and jejunal specimens. The Wilcoxon matched pairs signed rank-sum test was used to compare the proportion of T-cell subsets in different mucosal compartments within each group.
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Results |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Normal Nasal Mucosa
T cells. CD3+ LPLs were observed as single cells or in small clusters located mainly in the subepithelial region. CD3+ IELs were distributed throughout the surface epithelium, but mainly basally. The median number of CD3+ IELs and LPLs per square millimeter of tissue was 588 (range, 185-898) and 642 (range, 315-1,136), respectively.
TCR expression.
Most CD3+ IELs and CD3+ LPLs
(> 90%) expressed TCR/, but a small fraction of each
(5 and 4%, respectively) expressed TCR/. The proportion of / cells was not significantly different in the two
mucosal compartments (Figure 1).
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CD4 and CD8 expression.
Most CD3+ cells in the surface epithelium (Figures 1a and 2) were CD8+ (64%), but
a substantial fraction (30%) expressed CD4. The CD8 phenotype was relatively more frequent in the glandular
epithelium (median, 86%; range, 72-97%; P = 0.007). In
addition, varying numbers of CD3CD4+ cells were seen
in the surface epithelium and in the lamina propria in most
specimens (Figure 2). Additional staining experiments revealed that most of these cells expressed HLA-DR (Figure 3) or CD68 (Figure 4), therefore belonging to the
monocyte/macrophage lineage. Conversely, CD8 expression was strictly confined to the CD3+ population.
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/ (decorated with the same color as CD4 and
CD8) in adjacent sections, showed that the / cells included most of the CD3+CD4CD8 phenotype because
very few (< 1%) CD3+/ CD4CD8 cells were seen.
T-cell differentiation and activation markers.
Because a
small fraction of putative immature T cells in the human
intestine lacks CD3 but expresses CD7 (17), we examined the expression of this differentiation marker in nasal mucosa. CD7 was common on T cells in both compartments
(Figure 5), although more frequently (P < 0.005) expressed by IELs than by LPLs (Figure 1). In addition, a
minor population of CD7+CD3 was observed (2 and 8%
of all intraepithelial and lamina propria T cells, respectively; Figure 5). These CD3 cells were usually CD7bright
and did not express the natural killer cell markers CD16 or
CD56 (data not shown). Most CD3+ IELs and LPLs expressed CD45RO and not CD45RA (Figure 1). The integrin E7 was more often expressed by IELs (Figures 1
and 6) than by LPLs (78 versus 20%). Additional staining
experiments revealed that E7 was mainly restricted to
the CD8 phenotype; this integrin was expressed by only
~ 35% of CD4+ IELs. The activation marker CD25 was in
most specimens not present on IELs and only on ~ 2% of
CD3+ LPLs.
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Epithelial adhesion molecules. Both the surface and the glandular epithelium showed uniformly strong positivity for E-cadherin in nasal mucosa (Figure 7). The surface epithelium was in all cases weakly positive for intercellular adhesion molecule 1 (ICAM-1; CD54) basolaterally (Figure 8 ), whereas the glandular epithelium was always negative for this adhesion molecule.
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Normal Jejunal Mucosa
Except for the proportions of CD4+ and CD8+ T cells, the expression of most T-cell markers determined in nasal mucosa accorded well with similar data available from several previous studies on human jejunal T cells (17), including work from our laboratory applying the same staining technique as in the present study (20). Therefore, we decided to examine comparable tissue compartments of both mucosae in parallel with our two-color immunofluorescence staining technique, particularly focusing on the CD4:CD8 ratio.
T cells. The proportion of CD8+ T cells was significantly increased in the villus epithelium (median, 83%) compared with that in the nasal surface epithelium (Figure 1a), whereas the situation was opposite for CD4 (10%). In the lamina propria, the CD4 phenotype dominated significantly more in the jejunal (73%) than in the nasal mucosa, whereas the intestinal proportion of CD8+ T cells (30%) was reduced (Figure 1b).
Epithelial adhesion molecules. Both the villus and crypt epithelia showed uniformly strong positivity for E-cadherin in jejunal mucosa, whereas both epithelial elements in all cases were negative for ICAM-1 (not shown). Thus, the result for ICAM-1 was strikingly different from that obtained in nasal mucosa.
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Discussion |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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This study reports for the first time two- and three-color immunofluorescence in situ phenotyping of T cells in histologically normal nasal mucosa. In agreement with previous data obtained with immunohistochemical single staining (11, 12, 15), we found that most T cells were located in the superficial stroma and in the surface epithelium. The lamina propria contained T cells at a density (642/mm2) similar to that determined in two previous studies (12, 15), but our figure was higher than that of Fokkens and coworkers (11) both in the lamina propria and in the surface epithelium. This difference could be explained at least in part by the large individual variations (up to 100-fold) in T-cell number in the latter study compared with our data (less than 5-fold variation).
With respect to the CD4:CD8 T-cell ratio in normal nasal mucosa, the literature contains highly conflicting results. An early study by Winther and coworkers (15) reported that more than 70% of the T cells both in the
surface epithelium and in the lamina propria expressed
CD4, but these observations have been contradicted by
others (11, 14). We found approximately twice as many
CD3+CD8+ as CD3+CD4+ in the surface epithelium and
only a slight predominance of T cells expressing CD4 in
the lamina propria; these data are similar to those reported by Fokkens and coworkers (11). The large variability in the reported CD4:CD8 ratios may have several explanations and particularly be caused by the different
immunohistochemical techniques applied. In the single
staining study by Winther and coworkers (15), the sum of
CD4+ and CD8+ cells exceeded by far the number of cells
positive for CD3; this discrepancy might be explained by
the fact that not only T cells but also some resident macrophages express CD4. Such expression might likewise
contribute to the high fraction of CD4+ cells taken to be
T-lymphocytes by others (10, 12, 21). Indeed, with three-color immunofluorescence staining we always observed a
variable number of CD4+CD3 cells in both mucosal compartments, some with a morphology similar to lymphocytes. Most of these cells turned out to be of the monocyte/ macrophage lineage. By our immunofluorescence method
we were able to ensure that the sum of CD4+ and CD8+
T cells, with the addition of a small number of double-negative /+ T cells, equaled the total number of CD3+ cells.
This finding was further documented by decorating virtually the entire CD3+ population with a mixture of mAbs to
CD4, CD8, and /.
In agreement with previous reports (2, 17), we found that only 10% of jejunal CD3+ IELs expressed CD4, which was similar to the average fraction observed in nasal glands (14%). However, this finding contrasted with the relatively large proportion of CD4+ (30%) T cells detected in the surface epithelium of nasal mucosa. The latter was more like the situation reported for the follicle-associated epithelium of human Peyer's patches (22). Furthermore, as opposed to the jejunal epithelium (23; and this study), we showed that the potentially costimulatory molecule ICAM-1 often was expressed on nasal surface epithelial cells in the normal situation, as reported previously also by others (24).
Therefore, it is tempting to speculate that different immunoregulatory mechanisms operate at the two mucosal sites. In vitro experiments have in fact demonstrated that intestinal epithelial cells can induce proliferation of CD8+ T cells with suppressor effect, whereas HLA class II+ respiratory epithelial cells preferentially induce proliferation of CD4+ T cells (25, 26). The predominating CD8+ IELs in the intestine may hence contribute to the normal hyporesponsiveness (oral tolerance) existing against harmless soluble dietary antigens, whereas help rather than suppression may result from interactions between IELs and epithelial cells in the upper airways (4). Such local immunoregulatory disparity could partly explain preferential development of upper airway allergy through break of tolerance to inhalant antigens.
In our study, 55% of nasal lamina propria T cells expressed CD4, which is lower than the approximately 70% of this phenotype observed for jejunal LPLs (19; and this study). Assuming that similar subset proportions are recruited to both mucosal sites, the relatively reduced CD4 representation in the nasal lamina propria might reflect increased migration of this subset into the epithelium. However, it appears that site-specific mechanisms exist for lymphocyte homing (3). Although this phenomenon has been best studied for the intestine (3), similar selective mechanisms may to some extent be unique for the upper airways. Interestingly, it has been shown that human lung T cells either lack or bear very few of the homing receptors involved in lymphocyte recruitment to the skin, gut, and peripheral lymph nodes (27).
Integrin E7 is expressed on most intestinal IELs (2,
17); this adhesion molecule mediates binding to E-cadherin on epithelial cells (5). Our results suggested that a
similar mechanism exists for retention of CD8+ T cells
within the nasal epithelium; almost 80% of nasal IELs were positive for E7, particularly the CD8+ subset, and
the nasal epithelium showed strong staining for E-cadherin. However, because only 35% of the CD4+ IELs expressed E7, other (or additional) mechanisms must explain their retention within the epithelium. In this respect
it was interesting to observe that the surface (but not the
glandular) epithelium expressed ICAM-1. This adhesion
molecule may act as a ligand for leukocyte function-associated molecule 1(LFA-1) (L2, or CD11a/CD18) expressed by T cells and thereby contribute to the relatively
large CD4+ subset in the nasal surface epithelium.
In pediatric patients, Graeme and coworkers (13) reported that nasal IELs rarely are positive for E7 and often negative for CD7, whereas we showed that these cells
mostly express both markers as do intestinal IELs (2, 17).
This striking discrepancy might have a technical explanation, although some variation caused by age differences
could not be fully excluded. A small proportion of human
intestinal lymphocytes does not express any lineage differentiation antigens except CD7, which may represent an
early T-cell marker (17). In situ triple staining enabled us
to identify a small CD7bright subset that expressed neither
other T-cell markers nor the natural killer cell markers
CD16 and CD56. This phenotype might represent an immature T cell or be an unusual type of natural killer cell proposed to occur in human gut mucosa (17).
The proportion of T cells expressing / is higher in the
jejunal epithelium than in the gut lamina propria (17, 28), and / IELs are believed to play a special role in immune
surveillance and repair of damaged epithelium (7). Most
nasal CD3+ IELs and LPLs expressed TCR/ and only a
few were positive for TCR/. Both within the surface epithelium and in the lamina propria the latter phenotype
showed a proportion similar to that seen in peripheral
blood. Thus, there was no predilection of nasal / T cells
for the epithelium in contrast to the situation in the gut.
However, an increased number of / IELs has been reported in patients with perennial allergic rhinitis, suggesting a role for this subset in allergy (29). Furthermore, most
nasal T cells displayed the CD45RO+CD45RA phenotype, reflecting prior antigen priming (30). This was similar to intestinal IELs and contrasted with the phenotype in peripheral blood, where CD45RA+ T cells predominate
(19).
Phenotypic in situ studies of T cells in the lower respiratory tract have suggested that the subset composition is
similar to that in the upper airways: CD4+ cells predominate over CD8+ cells in the lamina propria (31, 32),
whereas the reverse is found in the epithelium (33). Furthermore, most LPLs and IELs in the lower respiratory
tract express TCR/ and are CD45RO+ (34, 35) and
IELs generally bear E7 and CD7 (36, 37).
In conclusion, this study has extended previous knowledge on mucosal T cells in the normal human upper airway. The phenotypes show several similarities to those of normal jejunal mucosa, but two striking differences were noted: CD4+ T cells were relatively increased in the epithelium and decreased in the lamina propria. It should be determined whether these differences, perhaps in combination with an abundant epithelial expression of adhesion molecules, might contribute to the relatively high frequency of persistent allergic reactions in the airways compared with the gut.
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Footnotes |
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Address correspondence to: Frode L. Jahnsen, LIIPAT, Rikshospitalet, N-0027 Oslo, Norway. E-mail: frode.jahnsen{at}rh.uio.no
(Received in original form April 15, 1997 and in revised form September 4, 1997).
Acknowledgments: The authors thank Drs. H. Stein and P. C. L. Beverly for providing mAbs BerAct8 and UCHL-1, and the technical staff at LIIPAT for excellent assistance. Studies in the authors' laboratory have been supported by the Norwegian Cancer Society, the Research Council of Norway, the Research Fund for Asthma and Allergy, and the Red Cross Research Fund for Children with Asthma and Allergy.
Abbreviations AMCA, 7-amino-4-methylcoumarin-3-acetic acid; Cy-3, indocarbocyanine; IELs, intraepithelial lymphocytes; LPLs, lamina propria lymphocytes.
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References |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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