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Specific Vß T Cell Subsets Are Associated with Cat and Birch Pollen Allergy in Humans¹

Kirsten Beyer^2,*, Tom Häusler^*, Moritz Kircher, Renate Nickel^*, Ulrich Wahn^* and Harald Renz

^* Department of Pneumology/Immunology, Children’s Hospital, Berlin, Germany; and Institute of Laboratory Medicine and Pathobiochemistry, Charité-Campus Virchow-Klinikum of Humboldt University, 13353 Berlin, Germany

	Abstract

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Cognate interaction between TCRs and MHC class II molecules plays an important role in initiating the allergen-specific immune response. Therefore, we analyzed the TCR distribution of human PBLs of 56 atopic and nonatopic (NA) individuals, including 4 monozygotic twin pairs, from two extended and four nuclear families. The expression of 23 Vß and 3 V elements was analyzed. The blood samples of symptomatic birch pollen-sensitized individuals that were taken 6 wk after the birch pollen season (n = 8) showed a significantly higher frequency of Vß16.1⁺ and Vß20.1⁺ T cells compared with the blood samples of birch pollen-sensitized individuals that were obtained out of allergen season (n = 10) or from NA individuals (p < 0.0005 and p < 0.0001, respectively). Allergen-specific lymphocyte proliferation was detected in the allergic individuals, and the distribution of Vß16.1⁺ and Vß20.1⁺ T cells returned to normal levels after the pollen season. The frequency of these Vß-expressing T cells correlated with the levels of allergen-specific IgE Abs. In addition, cat-sensitized individuals (n = 8) showed a significantly higher frequency of Vß17.1-expressing T cells than did NA individuals (p < 0.005). Our results indicate restricted TCR-Vß gene usage in cat and birch pollen allergies; we suggest that both genetic and environmental factors contribute to TCR-Vß gene expression and to the development of a specific T cell response.

	Introduction

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The interaction between APCs and T cells is crucial for initiating the allergen-specific immune response. The Ag specificity of T cells is determined via TCR expression. In humans, the majority of T cells express TCR-ß. - and ß-chains are composed of a V and a C region. Despite the great diversity in the TCR-ß repertoire, many Ag-specific responses demonstrate the dominance of few specific TCR combinations (1, 2, 3, 4, 5, 6, 7). The TCR repertoire of mature circulating T cells appears to be genetically determined: Highly similar profiles of TCR-V and -Vß usage among monozygotic twins as opposed to siblings and unrelated individuals have been reported (8, 9, 10, 11, 12). However, significant differences in TCR distribution can appear if only one identical twin is affected by certain immunologic disorders (13, 14). Environmental factors also shape the TCR repertoire (15, 16). It has been reported that TCR V-gene usage at birth seems to be nearly identical in two cohorts of distinctly different ethnic origin (17). These results suggest a considerable influence of the environment on the final maturation of the adult TCR repertoire.

Because the development of an allergen-specific T cell response represents a hallmark in allergenic immune responses, we previously examined this response in an animal model of airway sensitization. It was shown that specific Vß T cell subsets mediated the immediate hypersensitivity response to certain allergens, including OVA (1) and ragweed (18). Based on these animal studies, we investigated in humans whether allergies to pollen or pets were associated with an increase of certain TCR-Vß-expressing T cells in the peripheral blood of allergic patients. We subsequently considered whether the usage of these TCR-Vß subsets is genetically determined within families with a large number of atopic individuals.

	Materials and Methods

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Study population

A total of 56 individuals, including 4 monozygotic twin pairs, from two extended and four nuclear families participated in this study. The families were chosen because of their high frequency of atopy. Ages ranged from 3 to 78 years. A total of 37 individuals were atopic. These individuals suffered from bronchial asthma (n = 13), allergic rhinitis (n = 24), and/or atopic dermatitis (n = 13), based on the diagnosis of a physician. Total IgE concentrations ranged from 2 to 1593 kU/l (mean 306.2 kU/l). Table I shows the characteristics of the birch pollen- and cat-allergic individuals. Individuals who were sensitized to the seasonal outdoor allergen birch pollen were divided into two groups: in one group, blood was sampled during or 6 wk after allergen season; in the other group, blood was sampled out of the specific allergen season. The other 19 individuals were NA, with a negative history of allergic symptoms. Total IgE ranged from 3.3 to 152 kU/l (mean 32.9 kU/l). Specific IgE against common aeroallergens was not detectable (<0.35 kU/l). Four monozygotic twin pairs participated in the study. Their characteristics are summarized in Table II. Informed consent was obtained, and the study was approved by the local ethics committee.

Expression of V and Vß

The expression of the TCR-V and -Vß repertoire on peripheral T cells was assessed by flow cytometry using 25 mAbs. mAbs recognizing TCR-V24.1, -Vß2.1, -Vß3.1, -Vß5.1, -Vß5.2, -Vß5.3, -Vß6.1, -Vß8.1/8.2, -Vß11.1, -Vß12.2, -Vß13.1, -Vß13.6, -Vß14.1, -Vß16.1, -Vß17.1, -Vß18.1, -Vß20.1, -Vß21.3, and -Vß22.1 were obtained from Immunotech (Hamburg, Germany). mAbs against V2.3, V12.1, Vß6.7, Vß12.1, and Vß13.1/13.3 were obtained from DPC Biermann (Bad Nauheim, Germany). mAbs against Vß9.1 were obtained from PharMingen (San Diego, CA). Each Ab was FITC-labeled and used in a concentration recommended by the manufacturer. Peripheral EDTA-blood was incubated with anti-V/Vß Abs for 30 min at 4°C in the dark. After lysing RBCs and washing three times with PBS (10 min, 1000 rpm, room temperature), the cells were resuspended in TRIS buffer. A total of 1 x 10⁴ cells per sample was analyzed on a FACScan flow cytometer (Becton Dickinson, Heidelberg, Germany) using a gate for lymphocytes. To determine the frequency of TCR-V/Vß-expressing T cells, distributions of TCR-V/Vß elements were calculated and expressed as a percentage of CD3⁺ cells (as determined by staining with anti-CD3 mAb, Becton Dickinson).

Proliferation assay

PBMCs were purified from heparinized blood by density-gradient centrifugation on a Lymphoprep (Biotest, Darmstadt, Germany). PBMCs (2 x 10⁵) were cultured in triplicate in 96-well plates (200 µl) in the presence or absence of Ag in RPMI 1640 (Biochrom, Berlin, Germany) supplemented with 10% heat-inactivated FCS (Behringwerke AG, Marburg, Germany), 2 mM glutamine (Biochrom), 100 units/ml penicillin (Biochrom), 100 µg/ml streptomycin (Biochrom), and 0.2 µg/ml amphotericin B (Life Technologies, Gaithersburg, MD). Bet v 1 (50 µg/ml) (ALK, Copenhagen, Denmark) was used to determine Ag-specific proliferation. PWM (1 µg/ml) (Sigma, St. Louis, MO) was used as a positive control. After 4 days of culture (37°C, 5% CO₂), cells were pulsed with [³H]thymidine (0.5 µCi per well) (Amersham, Arlington Heights, IL) for 16 h. The incorporated radioactivity was measured by scintillation counting. The stimulation index (SI) was defined by the ratio of mean cpm of stimulated to unstimulated cultures.

Determination of total and specific serum IgE

Concentrations of total and allergen-specific IgE Abs were determined by fluorescent enzyme immunoassay using the Pharmacia CAP system (Pharmacia, Uppsala, Sweden) (19). The detection limit was 0.35 kU/L.

Statistical analysis

Nonparametric analysis (Mann-Whitney U test) was performed to assess differences in TCR distribution between blood samples. Nonparametric Spearman’s rank correlation was used to test for a correlation between Vß expression and specific IgE measurements. Differences associated with p values of <0.05 were considered significant.

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
To compare the TCR-Vß and -V repertoire in the peripheral blood of atopic and nonatopic (NA)³ individuals, the TCR distribution of 37 atopic and 19 NA family members was analyzed. Fig. 1 shows the normal TCR distribution according to our NA study population. In comparison with these NA individuals, a significantly different TCR distribution was found in allergic individuals sensitized against birch pollen or cat allergens. As shown in Fig. 2, birch pollen-allergic individuals during allergen season (BA⁺ group, n = 8) showed a significantly higher frequency of Vß16.1- and Vß20.1-expressing T cells compared with birch pollen-allergic individuals out of allergen season (BA^- group, n = 10) or NA individuals (NA group, n = 19) (p < 0.0005 and p < 0.0001, respectively). All birch pollen-allergic individuals suffered from allergic rhinitis and/or bronchial asthma. Interestingly, the two individuals who expressed the lowest values of Vß16.1 and Vß20.1 in the BA⁺ group (Fig. 2) were the individuals with blood sampling at 5–6 wk after the birch pollen season. One extended family over three generations with birch pollen-allergic and nonallergic family members is shown in Fig. 3 along with their individual Vß16.1 levels. In addition, a significant correlation between the amount of birch pollen-specific IgE and Vß16.1 and Vß20.1 expression was observed during allergen season (p < 0.003 and p < 0.006, respectively, Fig. 4). To assess the allergen-specific T cell reactivity in these birch pollen-allergic individuals, stimulation with the major birch pollen allergen Bet v 1 was performed on PBMCs of three individuals from the BA⁺ group. Marked T cell proliferation was detected, with a SI around five (Fig. 5).

View larger version (29K): [in this window] [in a new window]   FIGURE 1. TCR-Vß distribution in the peripheral blood of 19 NA individuals. Expression on CD3+ T cells was assessed by flow cytometry using 22 Vß-specific mAbs.

View larger version (12K): [in this window] [in a new window]   FIGURE 2. Frequency of Vß16.1+ and Vß20.1+ T cells in BA+ individuals (n = 6), BA- individuals (n = 10), and NA individuals (n = 19). The two arrows mark the two individuals with blood drawn between 5 and 6 wk after birch pollen season. Expression on CD3+ T cells in the peripheral blood was assessed by flow cytometry using mAbs for TCR-Vß16.1 and -Vß20.1.

View larger version (21K): [in this window] [in a new window]   FIGURE 3. Frequency of Vß16.1-expressing T cells in birch pollen-allergic (filled symbols) and nonallergic (open symbols) family members from one extended family. Expression on CD3+ T cells in the peripheral blood was assessed by flow cytometry using mAb recognizing TCR-Vß16.1. The values are shown below each subject. The normal range for Vß16.1 according to our NA study population is 0–2.2%. The double arrows mark the BA+ individuals. Blood from BA- individuals was drawn out of season; blood from nonsensitized family members was drawn in as well as out of birch pollen season.

View larger version (15K): [in this window] [in a new window]   FIGURE 4. Association of Vß20.1 and birch pollen-specific IgE levels during allergen season. Expression of Vß20.1 on CD3+ T cells in the peripheral blood was assessed by flow cytometry using mAbs. Birch pollen-specific IgE was determined by fluorescent enzyme immunoassay using the Pharmacia CAP System. CAP classes were determined by Pharmacia (CAP class 0, <0.35 kU/l; CAP class 1, 0.35–0.7 kU/l; CAP class 2, 0.7–3.5 kU/l; CAP class 3, 3.5–17.5 kU/l; CAP class 4, 17.5–50.0 kU/l; CAP class 5, 50.0–100.0 kU/l; and CAP class 6, >100.0 kU/l).

View larger version (21K): [in this window] [in a new window]   FIGURE 5. Proliferation of PBMCs from birch pollen-sensitized individuals after stimulation with the major birch pollen allergen Bet v 1, PWM, or medium alone. Blood samples were obtained from the three subjects with the highest Vß16.1 and Vß20.1 levels to determine the T cell proliferative response of the birch pollen-allergic individuals to birch pollen allergen. PBMCs were purified from heparinized blood and cultured in the presence or absence of Bet v 1 or PWM. [3H]thymidine incorporation was measured. The SI was defined by the ratio of mean cpm of stimulated to unstimulated cultures.

View larger version (32K): [in this window] [in a new window]   FIGURE 6. Frequency of Vß16.1+ and Vß20.1+ T cells obtained during the birch pollen season compared with cells from the same individual obtained out of birch pollen season in four birch pollen-allergic individuals. Expression of Vß on CD3+ T cells in the peripheral blood was assessed by flow cytometry using Vß-specific mAbs.

View larger version (16K): [in this window] [in a new window]   FIGURE 7. Frequency of Vß17.1+ T cells in cat-allergic and NA individuals. Expression on CD3+ T cells in the peripheral blood was assessed by flow cytometry using mAbs recognizing TCR-Vß17.1.

View larger version (29K): [in this window] [in a new window]   FIGURE 8. Frequency of Vß16.1+ and Vß17.1+ T cells in one of four pairs of identical twins. One brother was sensitized against birch pollen; his twin was sensitized against cat. Expression on CD3+ T cells in the peripheral blood was assessed by flow cytometry using mAbs recognizing TCR-Vß16.1 and -Vß17.1.

View larger version (33K): [in this window] [in a new window]   FIGURE 9. Vß repertoire of two nonsensitized pairs of twins. Expression of TCR-Vß on CD3+ T cells in the peripheral blood was assessed by flow cytometry using Vß-specific mAbs. TCR-Vß distribution between monozygotic twins is virtually identical.

	Discussion

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The monozygotic twin studies suggest that allergen exposure alone cannot completely explain the enhanced expression of certain Vß⁺ cells. All twin pairs lived under the same environmental conditions, yet showed different behavior of TCR repertoire in response to the allergen. Only individuals that developed an IgE response to the allergen had increased specific Vß expression. The same phenomenon was found in the extended families, which were selected on the basis of a high prevalence of atopy. For birch pollen allergen, elevated frequencies of Vß16.1- and Vß20.1-expressing T cells were detected only among atopic family members that had IgE Abs against the allergen. However, not all of those individuals showed elevation of these Vß T cells; elevated frequencies were only seen in family members who were exposed to allergen in season. In addition, we found no NA subjects who showed TCR-Vß16.1 and -Vß20.1 usage above the normal range. These findings suggest that other factors contribute to the expression of the TCR-Vß phenotype in addition to environmental conditions. Moffatt et al. have suggested that certain TCR genes of the TCR- complex are linked to specific IgE responses (21). Specific IgE reactions might be constrained by variability in the HLA or TCR proteins, because HLA-peptide presented to the TCR represents the specific cognate signal governing the development of a specific IgE response. Moffatt et al. studied British and Australian subjects, whereas we present results from individuals with bilateral German ethnicity. In addition, this group did not study the IgE responsiveness to birch pollen or cat allergen. These differences in study designs may account for their finding of TCR- gene linkage rather than the TCR-ß expression that we describe. In our study, a positive correlation between the frequencies of Vß-expressing T cells and the amount of Abs further suggests a close relationship between TCR gene usage and the development of allergen-specific IgE responses in atopic individuals. Moffatt’s recessive genetic effect for IgE response and atopy had been proposed previously (22, 23). Our data are certainly compatible with a recessive trait pattern, but do not definitely confirm such a trait.

Several studies have described a restricted expansion of Vß subsets in certain autoimmune or infectious diseases (16, 24, 25, 26, 27, 28). In contrast to this superantigen-driven TCR-Vß expansion, there are few authors reporting the capacity of classic Ags to selectively expand particular TCR-Vß gene product-expressing T cells. Werfel et al. found a restricted Vß repertoire in nickel-mediated contact dermatitis (29). In response to a short ragweed allergen, Amb a 5, a dominant TCR-ß-chain, was observed in two unrelated subjects of different race (7). Another group showed that CD4⁺ T cells in atopic individuals sensitized to the house dust mite primarily expressed TCR-Vß3 and -V8 genes (30).

In a mouse model of allergen-specific IgE responses, airway inflammation, and airway hyperresponsiveness, it was recently shown that development of this allergic phenotype depended upon certain TCR-Vß-expressing T cells; for example, the response to OVA was mediated by Vß2-, Vß8-, and Vß14-expressing T cells (18). Ragweed sensitization depended upon Vß9⁺, Vß8⁺, Vß13⁺, and Vß14⁺ T cells; even more importantly, the IgE phenotype could be transferred from sensitized into nonsensitized animals with certain Vß subsets (1). In addition, the in vivo accumulation of TCR-Vß-expressing T cells correlated with in vitro expansion of the same T cell subsets (1).

These collective data increasingly support the capacity of classic Ag, without apparent superantigen activity, to selectively expand particular TCR-Vß gene product-expressing T cells in humans. This finding is in contrast to the common interpretation up until several years ago that selective expansions based on TCR-Vß gene products might reflect a superantigen drive.

In conclusion, we were able to identify expanded populations of T cells expressing the same TCR-Vß-chains in birch pollen- and cat-allergic individuals. In birch pollen-allergic individuals, this observation was restricted to the birch pollen season, which shows the importance of Ag exposure in shaping the TCR repertoire. In addition, intrinsic nonenvironmental and genetic factors also contribute to the individual TCR-Vß-dependent immune response pattern in atopic individuals. Further studies are required to determine whether TCR-Vß elements may be a useful marker for such atopic individuals, and whether these results can be used to design a specific therapy acting at the MHC-peptide-TCR level.

	Acknowledgments

 
We thank Margret Oberreit-Meneses, Petra Ellenson, and Gabi Schulz for excellent technical support.

	Footnotes

 
¹ This work was supported by the Deutsche Forschungsgemeinschaft (DFG Grant No. Re737/4-3 and 4-4).

² Address correspondence and reprint requests to Dr. Kirsten Beyer, Mount Sinai Medical Center, Division of Pediatric Allergy and Immunology, Box No. 1198, One Gustave L. Levy Place, New York, NY 10029-6574. E-mail address:

³ Abbreviations used in this paper: NA, nonatopic BA⁺, birch pollen-allergic individuals with blood samples obtained during or 6 wk after birch pollen season; BA^-, birch pollen-allergic individuals with blood samples obtained out of birch pollen season; SI, stimulation index.

Received for publication May 15, 1998. Accepted for publication September 25, 1998.

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