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Am. J. Respir. Cell Mol. Biol., Volume 22, Number 4, April 2000 405-411

Human Bronchial Intraepithelial T Lymphocytes as a Distinct T-Cell Subset
Their Long-Term Survival in SCID-Hu Chimeras

Eisuke Goto, Hirotsugu Kohrogi, Naomi Hirata, Kaori Tsumori, Susumu Hirosako, Junji Hamamoto, Kazuhiko Fujii, Osamu Kawano, and Masayuki Ando

First Department of Internal Medicine, Kumamoto University School of Medicine, Kumamoto, Japan


    Abstract
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References

Intestinal intraepithelial T lymphocytes (i-IELs) show features different from those of conventional T cells and play specific roles in the mucosal immunity. To investigate whether human bronchial intraepithelial T lymphocytes (IELs) are a distinct entity, we examined T cells in human bronchial xenografts transplanted on mice with severe combined immune deficiency (SCID). We transplanted human bronchi subcutaneously into mice with SCID, resected the xenografts after various incubation periods (7-174 d), and examined them for CD3+, CD4+, CD8+, and CD45+ cells by immunohistochemistry. The number of CD3+ cells in the lamina propria decreased significantly in the first month (from 308.7 ± 60.2 to 70.9 ± 49.4/mm2; P < 0.05), and xenografts more than 5 mo of age had scant T cells in the lamina propria (5.2 ± 2.0/mm2). However, there was no significant difference between the number of CD3+ IELs in freshly isolated bronchi and in xenografts maintained for more than 5 mo. In freshly isolated bronchi, the number of CD4+ IELs was significantly lower than that of CD8+ cells (2.35 ± 0.62 versus 4.56 ± 1.32/mm basement membrane; P < 0.01). After transplantation, the mean CD4-to-CD8 ratio of all xenografts was significantly higher than that of freshly isolated bronchi (5.2 ± 0.9 versus 0.6 ± 0.2; P < 0.005). The IELs were positive for CD45, which is specific for human leukocytes, and they were eliminated by irradiation before the transplantation. Almost all IELs (99.5%) in the xenografts expressed alpha beta T-cell receptor, and 35.8% of IELs expressed alpha ebeta 7 integrin. Bronchial epithelial cells in the xenografts expressed interleukin (IL)-7, stem cell factor, intercellular adhesion molecule (ICAM)-1, and human leukocyte antigen-DR (HLA-DR). We conclude that in the SCID-Hu chimera model, human bronchial IELs survive for more than 5 mo, unlike the T cells in the lamina propria, and we suggest that human bronchial IELs may be stimulated by bronchial epithelial cells expressing IL-7, stem cell factor, ICAM-1, and HLA-DR.


    Introduction
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References

Intraepithelial T lymphocytes (IELs) are observed in the epithelial layer lining the body surface. Especially, intestinal IELs (i-IELs) show functional features of a distinct T-cell subset in their ontogeny, phenotype, usage of T-cell receptors (TCR), and functions (1, 2). For example, more than 95% of i-IELs express alpha ebeta 7 integrin, whereas fewer than 5% of peripheral blood T cells express this molecule (1, 3). Thus, alpha ebeta 7 integrin is regarded as an i-IEL-specific adhesion molecule. IELs are also observed in the human bronchial epithelium (3, 4), and although alpha ebeta 7 integrin-positive cells exist there, they constitute a lower percentage of bronchial IELs than of i-IELs (3). Additionally, in contrast to i-IELs, usage of gamma delta TCR by bronchial IELs is quite low (5). Because further characteristics of human bronchial IELs are not known, it has not been concluded whether bronchial IELs are a distinct entity.

Interleukin (IL)-7 (6), stem cell factor (6, 9), intercellular adhesion molecule (ICAM)-1 (10), and major histocompatibility complex class II (11) are implicated in the growth of IELs, and they support the long-standing survival of T cells. However, the interactions between the human bronchial epithelium and IELs are not well characterized.

To address these issues, we used a severe combined immune deficiency (SCID)-Hu chimera model into which human bronchial tissues were transplanted. Mice with SCID are immunodeficient mice lacking functions of T and B lymphocytes (12, 13). Because mice with SCID do not reject xenografts, many models using transplants of human tissues, including bronchial tissues, have been studied (14- 17). These models are very useful because using them, long-term human tissue culture systems are available.

Using mice with SCID in the present study, we found that bronchial IELs survived for more than 5 mo in the epithelial layer of human bronchial xenografts, whereas T cells in the lamina propria of the xenografts rapidly disappeared. Further, epithelial cells in the xenografts expressed IEL-associated growth factors and surface molecules, including IL-7, stem cell factor, ICAM-1, and human leukocyte antigen (HLA)-DR. Thus, human bronchial IELs may survive in bronchial xenografts, stimulated by the epithelial cells.

    Materials and Methods
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References

Tissue Preparation

Human bronchial tissues were obtained from 29 patients (17 smokers, 12 nonsmokers) undergoing surgery for lung cancer. The patients did not have complaints suggesting underlying pulmonary diseases, including chronic bronchitis, asthma, and emphysema, and their chest roentgenograms were normal except for lung cancer. Their pulmonary functions (vital capacity and forced expiratory volume in 1 s) were within normal limits. All of the smokers stopped smoking at least 1 mo before the resection. Informed consent was obtained from the patients and their families. Immediately after the lung or lobe was resected, the tissues were placed in Krebs-Henseleit solution. Airway segments from the third- to fifth-generation bronchi, which were macroscopically normal, were cut into 10-mm lengths as bronchial rings. All tissues were prepared within 2 h after the resection.

  As control samples, freshly isolated bronchial tissues from six patients with lung cancer (three smokers, three nonsmokers) were used for immunohistochemistry.

Xenotransplantation and Harvesting

After anesthetizing 5- to 10-wk-old mice with SCID (CLEA Japan Corp., Tokyo, Japan) with pentobarbital (1.5 mg, intramuscularly), we made subcutaneous tunnels using a 10-mm incision on the abdomen. The prepared human bronchial rings were inserted into the tunnels, and the incisions were sutured. The xenografts were incubated for 7 to 174 d. After anesthesia, the xenografts were harvested and placed in optimal cutting temperature (OCT) embedding medium, snap-frozen in liquid nitrogen, and stored at -80°C until cryostat sectioning.

Immunohistochemical Staining

The frozen tissues were cut 6 µm thick and were stained immunohistochemically as previously described (18). Antibodies and reagents used for staining are listed in Table 1. For a peroxidase- dependent, brown color reaction, 3,3'-diaminobenzidine (Dojin, Kumamoto, Japan) was used as substrate. For an alkaline phosphatase-dependent color reaction, vector red or vector blue substrate kits (Vector Laboratories, Inc., Burlingame, CA) were used. Intrinsic alkaline phosphatase activity was blocked with levamisole (Vector Laboratories, Inc.). In the peroxidase-dependent staining, the tissues were counterstained with Mayer's hematoxylin.

                              
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TABLE 1
Antibodies for immunohistochemistry

Microscopic Assessment and Quantification of CD3+, CD4+, and CD8+ T Cells

The stained sections were examined with a VANOX AHBS3 microscope (Olympus, Tokyo, Japan). We counted CD3+, CD4+, and CD8+ T cells that were positively stained with the respective antibodies in the epithelial layer and lamina propria by using NIH Image Software, and we expressed the number of T cells in the epithelium (IELs) per 1 mm of basement membrane and the number of T cells in the lamina propria per mm2. We also counted alpha ebeta 7 integrin-positive cells and CD3+ cells in the serial sections, and expressed the results as the percentage of alpha ebeta 7 integrin-positive cells in the CD3+ cells.

Detection of CD45+ Cells in the Xenografts

Mice with SCID do not have functional T cells (12); however, they have cryptopatches that generate i-IELs in their intestines (6). To exclude the possibility that the IELs in the human bronchi were originated from mouse, we stained the tissues with antihuman CD45 antibody as described previously. The antihuman CD45 antibody was specific for human leukocytes because absence of cross-reactivity with SCID mice of the antibody was verified by immunohistochemical staining of trachea, lung, skin, liver, spleen, and intestine and further flow cytometric analysis of bronchoalveolar lavage fluid, peritoneal lavage fluid, and peripheral blood of mice with SCID.

Effect of Irradiation on CD3+ Cells in the Human Bronchial Xenografts

We prepared three sets of paired size and generation-matched human bronchial tissues. To delete the lymphocytes in the bronchial tissues, we placed one of each pair in Krebs-Henseleit solution in 24-well tissue culture plates, irradiated them with 10 Gy, and then transplanted them as described previously. The xenografts were harvested 3 mo after the transplantation, and the tissues were stained for CD3.

Statistical Analysis

Data are expressed as means ± standard error of the mean (SEM). Student's t test was used to analyze statistical differences. P < 0.05 was taken as statistically significant.

    Results
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References

Kinetics of CD3+ T Cells in Human Bronchial Xenografts

In the freshly isolated human bronchi, i.e., in the tissues before transplantation, CD3+ T cells were observed in both the intraepithelium (10.7 ± 2.1/mm BM) and the lamina propria (308.7 ± 60.2/mm2) (Figure 1a). Most IELs were present adjacent to the basement membrane.


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  		Figure 1.   Immunohistochemical staining for CD3 in freshly isolated human bronchi (a), and xenografts at 21 d (b) and 140 d (c) after transplantation. In freshly isolated human bronchi, CD3+ T cells were observed in both the intraepithelium and lamina propria. In xenografts, CD3+ T cells in the lamina propria gradually disappeared, but CD3+ T cells in the intraepithelium remained. Bar = 50 µm.

In the xenografts, the number of T cells in the lamina propria was significantly decreased at 1 mo after the transplantation (70.9 ± 49.4/mm2; P < 0.05) and became very low after more than 5 mo (5.2 ± 1.2/mm2; P < 0.01) (Figures 1b, 1c, and 2a). On the other hand, the number of IELs was not changed in the xenografts harvested at more than 5 mo after the transplantation (Figure 2b). As previously described (16), epithelial sloughing was observed 1 wk after transplantation, and the epithelia consisted of a single layer of epithelial cells. Even in this period, CD3+ cells were residing adjacent to the basement membrane, then the epithelial cell gradually regenerated in 2 to 3 wk (data not shown).


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  		Figure 2.   Kinetics of CD3+ cells in human bronchial xenografts. The number of T cells in the lamina propria was significantly decreased after 1 mo (a). However, there was no difference between the number of intraepithelial T cells in freshly isolated bronchi and xenografts (b). The values shown are means ± SEM; n indicates the number of tissues examined. *P < 0.05, ** P < 0.01.

There was no significant difference in the number of IELs between the xenografts of nonsmokers and those of smokers (10.9 ± 3.0 versus 11.1 ± 2.4/mm BM).

Detection of CD45+ Cells in the Xenografts

The distribution of CD45+ cells in the epithelial layer was almost identical to that of CD3+ cells (Figure 3). Because the antihuman CD45 antibody was specific for human leukocytes, the CD3+ cells were originated from human xenografts.


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  		Figure 3.   Immunohistochemical staining for CD45. IELs in xenografts expressed human leukocyte-specific antigen CD45 (a). The distribution of CD45+ cells was almost identical to that of CD3+ cells (b). These are representative sections from five xenografts from SCID mice at 89 to 161 d after transplantation. Bar = 50 µm.

Effect of Irradiation on CD3+ Cells in the Human Bronchial Xenografts

In the irradiated xenografts, the number of CD3+ cells was significantly decreased compared with that in the nonirradiated xenografts (Figure 4).


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  		Figure 4.   (Left) The effect of irradiation of xenografts before transplantation. A dose of 10 Gy irradiation significantly reduced the number of IELs in human bronchial xenografts. Values shown are means ± SEM of three independent experiments. *P < 0.05.

Kinetics of CD4+ and CD8+ T Cells in IELs in Human Bronchial Xenografts

In freshly isolated human bronchi, the number of CD4+ IELs was significantly lower than that of CD8+ cells (2.35 ± 0.62 versus 4.56 ± 1.32/mm BM; P < 0.01) (Figure 5). After transplantation, mean CD4-to-CD8 ratio of all xenografts was significantly higher than that of freshly isolated bronchi (5.2 ± 0.9 versus 0.6 ± 0.2; P < 0.005). Compared with freshly isolated human bronchi, the number of CD4+ T cells in the xenografts aged for more than 5 mo was siginificantly higher and the number of CD8+ T cells was significantly lower in the time points from 2 to 3 mo (Figure 5c).


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  		Figure 5.   Kinetics of CD4+ and CD8+ T cells in IELs in human bronchial xenografts. Serial sections were stained for CD4 (a) and CD8 (b) (indicated by arrows) immunohistochemically. As the graph shows (c), in freshly isolated bronchi, the number of CD8+ IELs (open circles) was higher than that of CD4+ cells (closed circles) (*P < 0.05). Compared with freshly isolated human bronchi, the number of CD4+ IELs in the xenografts at more than 5 mo after the transplantation was significantly higher, and the number of CD8+ IELs was significantly lower at 2 to 3 mo after the transplantation (# P < 0.05). Additionally, mean CD4-to-CD8 ratio of all xenografts was significantly higher than that of freshly isolated bronchi (5.2 ± 0.9 versus 0.6 ± 0.2; P < 0.005). Values shown are means ± SEM; n indicates the number of tissues examined. Bar = 50 µm.

In freshly isolated human bronchi, the CD4-to-CD8 ratio was lower in smokers than in nonsmokers (0.29 ± 0.08 versus 0.93 ± 0.20/mm BM; P < 0.05), but in the xenografts, there was no significant difference in the CD4-to-CD8 ratio between smoker and nonsmoker (5.4 ± 1.2 versus 5.0 ± 1.6/mm BM).

Detection of alpha ebeta 7 Integrin and alpha beta /gamma delta T-Cell Receptor in Bronchial IELs

alpha ebeta 7 integrin-positive cells were observed in the intraepithelium where IELs were located in both freshly isolated human bronchi and bronchial xenografts (Figures 6a and 6b). There was no significant difference between the ratio of alpha ebeta 7 integrin-positive cells to CD3+ cells in freshly isolated human bronchi and xenografts (Figure 6c). There was no correlation between the age of xenografts and the ratio of alpha ebeta 7 integrin-positive cells to CD3+ cells (R2 = 0.012). Almost all IELs in freshly isolated human bronchi and xenografts were stained with anti-Pan TCR alpha beta recognizing constant region of TCR beta  chain. Less than 0.5% of IELs were stained with anti-gamma delta TCR recognizing constant region of TCR delta  chain (Figure 7).


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  		Figure 6.   Immunohistochemical staining for alpha ebeta 7 integrin. alpha ebeta 7 integrin-positive cells were observed mainly on IELs in both normal human bronchi (a) (indicated by arrows) and bronchial xenografts (b). There were no significant differences between the ratio of alpha ebeta 7 integrin-positive cells to CD3+ cells in freshly isolated bronchi and xenografts (c). These are representative sections from five xenografts from SCID mice at 89 to 161 d after transplantation. Bar = 50 µm.


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  		Figure 7.   Immunohistochemical staining for alpha beta and gamma delta TCR. IELs in xenografts were stained with anti-Pan TCR alpha beta (a) and with anti-Pan TCR gamma delta (b). Almost all IELs expressed alpha beta TCR, and less than 0.5% of IELs expressed gamma delta TCR. These are representative sections from five xenografts from SCID mice at 89 to 161 d after transplantation. Bar = 50 µm.

Immunostaining for IL-7, ICAM-1, and HLA-DR in Human Bronchi and Xenografts

IL-7 immunostaining was observed mainly on epithelial cells and smooth muscle cells (Figure 8). Stem cell factor immunostaining was also detected with the same staining pattern as for IL-7 (data not shown). The distributions of IL-7 immunostaining in xenografts were similar to those in freshly isolated human bronchi (data not shown). ICAM-1 immunostaining was observed on the epithelial cells and endothelial cells as previously described (19, 20). ICAM-1 immunostaining on the epithelial cells was highly positive on the basement membrane side (data not shown). HLA-DR and stem cell factor immunostaining was observed on epithelial cells as previously described (data not shown) (20).


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  		Figure 8.   Immunohistochemical staining for IL-7. IL-7 immunostaining was mainly observed in epithelial cells and smooth muscle cells (b) (isotype-matched control shown in a). No counterstaining was performed. These are representative sections from five xenografts from SCID mice at 89 to 161 d after transplantation. Bar = 50 µm.

    Discussion
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References

We found in the present study that (1) IELs in human bronchial xenografts transplanted in mice with SCID survived more than 5 mo, (2) the surviving IELs were human T cells on which the CD4-to-CD8 ratio increased after transplantation, (3) IELs expressed alpha beta TCR (99.5%) and alpha ebeta 7 integrin (35.8%), and (4) the epithelial cells of the xenografts were positively stained with antibodies to IL-7, stem cell factor, ICAM-1, and HLA-DR.

i-IELs have many characteristics that are different from those of conventional T cells (1). Many features, including the high percentages of gamma delta TCR and CD8+ cells, their dependence for growth on IL-7 or stem cell factor (6, 7, 9), and the expression of specific adhesion molecule alpha ebeta 7 integrin (3) and the existence of i-IELs even in nu/nu mice (23), support the idea that i-IELs should be regarded as a distinct functional T-cell subset. However, bronchial IELs contain few T cells expressing gamma delta TCR (5), and the percentage of alpha ebeta 7 integrin-positive cells is quite low (3). Further, the difficulty of isolating human bronchial IELs has made it hard to characterize them. Therefore, it is not clear whether bronchial IELs are a counterpart of i-IELs.

SCID-Hu chimeras using human bronchial tissues give us the means to analyze the ontogeny and maintenance mechanisms of cells in human bronchial tissues. Because xenografts are supplied with nutrients and oxygen via recanalized blood vessels, the tissues in the SCID-Hu chimeras can be well maintained for much longer times than in ordinary tissue culture systems (16). In this study, before transplantation, many T cells were observed in the epithelium (IELs) and in the lamina propria of the bronchi. The T cells in the lamina propria rapidly disappeared after the transplantation. On the other hand, the IELs survived for more than 5 mo. The IELs were stained positively with antihuman CD45 antibody, which suggests that they were human leukocytes, and they were eliminated by irradiation before the transplantation. Therefore, the IELs were originated from the human bronchi. In mice, a special immunologic organ named the "cryptopatch" yields precursor cells for i-IELs (6, 9). Although in humans an organ like the cryptopatch has not been detected in the bronchi or the intestine, our data suggest the possibility that precursor cells may be residing in the bronchial epithelial layer. However, it is not possible to completely exclude that IELs derive from a precursor pool located elsewhere in the xenograft, e.g., the lamina propria and bronchus- associated lymphoid tissue. It is also not clear whether IELs persist in a resting state or whether these cells are turning with balance between proliferation and death. In the present study, CD4+ T cells increased at more than 5 mo after the transplantation, and CD8+ T cells decreased at 2 to 3 mo after the transplantation. The CD4-to-CD8 ratio of bronchial IELs increased after transplantation compared with before transplantation. We speculate that the reason for the results may be a decrease of stimulants such as smoke and/or irritants from the airway lumen because the CD4-to-CD8 ratio was significantly lower in the bronchi of smokers than in those of nonsmokers, which is consistent with the facts previously reported (24). Another possible explanation is that stimulation from the cells in the airway tissues is more effective for promoting survival of CD4 IELs than of CD8 IELs.

In mice, the number of gamma delta i-IELs is higher than that of alpha beta i-IELs, but in humans, the number of alpha beta i-IELs is higher than that of gamma delta i-IELs, even in intestine (1). In the normal human bronchi, gamma delta TCR-expressing T cells are rare, as shown in the present study and previous studies (5, 25). Additionally, almost all IELs in xenografts expressed alpha beta TCR. These data suggest that alpha beta T cells may play important roles in human bronchial mucosal immunity.

Because T cells were localized only in the epithelial layer in xenografts, there may be some interaction between IELs and bronchial epithelial cells. In the human intestinal tract, more than 95% of IELs express alpha ebeta 7 integrin (CD103) (3). It was suggested the interaction between alpha ebeta 7 integrin and its ligand, E-cadherin, played an important role in homing and localization of i-IELs at the intestinal epithelial layer because intestinal epithelial cells expressed E-cadherin (26). In the present study, however, only 35.8% of xenograft IELs expressed alpha ebeta 7 integrin. Therefore, the expression of alpha ebeta 7 integrin does not explain the interaction between IELs and the epithelium in the human bronchi.

We showed that epithelial cells in the human bronchi and xenografts expressed IL-7, stem cell factor, and ICAM-1. IL-7 is one of the cytokines important for the development of intestinal T cells in mice (8, 27). Precursor cells residing in the cryptopatches express IL-7 receptors and c-kit, so IL-7 and stem cell factor play critical roles in the development of i-IELs (6, 9). In humans, IL-7 causes proliferation of T cells (28, 29) and is produced by human intestinal epithelial cells (7) and keratinocytes (30). Thus, IL-7 regulates the proliferation of i-IELs. Further, an experiment using knockout mice showed that interaction between beta 2 integrin and ICAM-1 is necessary in the development of the i-IEL compartment (10). Therefore, we suggest that a microenvironment of the human bronchial epithelium expressing IL-7, stem cell factor, and ICAM-1 may promote the survival of IELs in the xenografts.

The present study demonstrated that MHC class II molecules are expressed on the epithelium of freshly isolated human bronchi and xenografts. i-IELs show oligoclonality in both alpha beta and gamma delta TCR (31), and in the human intestine, a group of gamma delta IELs recognizes stress-induced MHC-related molecules expressed on epithelial cells and, in turn, shows cytotoxicity (34, 35). Because human bronchial epithelial cells and xenografts expressed MHC class II molecules, as shown in the present study, and airway epithelial cells have accessory cell functions (36), it is possible that human bronchial epithelial cells present self or relevant antigens to T cells. MHC class II molecules are essential for the long-term life span of T cells in mice (11), and CD1d-mediated interactions between IELs and epithelial cells have also been reported (32, 37). Thus, complex and close interactions exist between IELs and the epithelium.

The roles of intestinal and bronchial IELs in diseases are yet not completely understood. i-IELs are increased in coeliac disease (38), and bronchial IELs are increased in chronic bronchitis (4). IELs are also necessary to regulate epithelial cell growth and maintain homeostasis (41, 42). Therefore, bronchial IELs may be associated with inflammatory diseases affecting airway epithelia, e.g., airway infections and bronchial asthma.

We conclude that, in the SCID-Hu chimera model, human bronchial IELs survive for the long term, unlike the T cells in the lamina propria, and we suggest that human bronchial IELs may be stimulated by bronchial epithelial cells expressing IL-7, stem cell factor, ICAM-1, and HLA-DR. The bronchial IELs may play important roles in airway mucosal immunity.

    Footnotes

Address correspondence to: Hirotsugu Kohrogi, M.D., First Department of Internal Medicine, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto 860-8556, Japan. E-mail: kohrogi{at}kaiju.medic.kumamoto-u.ac.jp

(Received in original form July 20, 1999 and in revised form October 8, 1999).

Presented in part at the April 1999 American Lung Association/American Thoracic Society International Conference in San Diego, CA.
Abbreviations: human leukocyte antigen, HLA; intercelluar adhesion molecule-1, ICAM-1; intraepithelial T lymphocytes, IELs; intestinal intraepithelial T lymphocyte, i-IEL; interleukin, IL; major histocompatibility complex, MHC; severe combined immune deficiency, SCID; T-cell receptor, TCR.

Acknowledgments: For their kind cooperation in providing human lung tissues, the authors thank Dr.Yoshioka of the First Department of Surgery, Kumamoto University School of Medicine; Drs. Kiyama, Fujino, and Saishoji of Kumamoto Chuoh Hospital; and Dr. Baba of Kumamoto City Hospital, as well as the entire staff of our department. This study was supported by Scientific Grants-in-Aid for Scientific Research (C) 10670553 and 06670622 from the Ministry of Education, Science and Culture of Japan.
    References
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Introduction
Materials and Methods
Results
Discussion
References

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