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Preferential Usage of TCR-V17 by Peripheral and Cutaneous T Cells in Nickel-Induced Contact Dermatitis¹

Lioba Büdinger^*,, Nicole Neuser^*, Uwe Totzke, Hans F. Merk^* and Michael Hertl^2,*,

^* Department of Dermatology and Interdisciplinary Center for Clinical Research, Rheinisch-Westfälische Technische Hochschule, Aachen, Germany; MDS Pharma Services, Hamburg, Germany; and Department of Dermatology, University ofErlangen, Erlangen, Germany

	Abstract

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Nickel (Ni) is one of the most common contact sensitizers in man, and Ni-induced contact dermatitis is considered as a model of hapten-induced delayed type hypersensitivity. Previous studies indicated that Ni-reactive T cells derived from Ni-allergic individuals preferentially express distinct TCR-V chains. However, data on the TCR-V repertoire of Ni-responsive T cells are not consistent. Therefore, the aim of this study was to identify the TCR-V receptors of Ni-responsive peripheral and cutaneous T cells in a cohort of 17 donors with Ni-induced contact dermatitis in comparison with those of 6 healthy controls. Peripheral NiSO₄-responsive T lymphocytes showed a significant overexpression of TCR-V17 and the frequency of TCR-V17⁺ T cells correlated significantly with the in vitro reactivity of PBMC to NiSO₄. In addition, the cutaneous infiltrate of Ni-induced patch test reactions consisted primarily of V17⁺ T cells. The majority of patch test-derived NiSO₄-responsive T cells of three allergic donors were TCR-V17⁺, whereas patch test-derived NiSO₄ unresponsive T cells of four additional donors did not express TCR-V17. Skin-derived Ni-responsive T cell lines from three donors uniformly secreted the Th2 cytokine, IL-5, but no IFN- or IL-10. These in vitro and in vivo findings strongly suggest that T cells with a restricted TCR-V repertoire, i.e., V17, predominate in NiSO₄-induced contact dermatitis and may be crucial in the effector phase of Ni hypersensitivity.

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References

 
Nickel (Ni) is one of the most common contact sensitizers causing delayed-type hypersensitivity in humans (1, 2, 3, 4). Accordingly, the cellular immune response to Ni²⁺ ions has become a model system for studying hapten-induced hypersensitivity (5, 6). There are two key processes in hapten-induced immune responses: presentation of the hapten in association with endogenous or exogenous peptides by HLA molecules on the surface of the APC, and recognition of the Ag-HLA-complex by the T cell via its specific Ag receptor (TCR).

In Ni-sensitized individuals, the first step in this sequence appears to be rather unselective, because Ni is not preferentially presented in association with distinct HLA-DR, -DQ, and -DP alleles (4, 6). Therefore, much of the interest has recently been focusing on T cell recognition and the nature of the epitopes formed by Ni²⁺ ions. Ni preferentially binds to cysteine and histidine residues of proteins/peptides and may be presented to T cells by processing-dependent and -independent pathways, as shown for other haptens (4, 6, 7). With regard to the structural characteristics of the TCR used by Ni-specific T cells, previous studies strongly suggested that only a limited TCR-V repertoire is expressed by Ni-responsive peripheral T cells (8, 9, 10, 11). However, the findings of the individual studies were inconsistent due to the different study designs and the small numbers of individuals investigated. Therefore, the aim of this study was a comprehensive analysis of TCR-V expression of Ni-specific T cells by examining peripheral as well as skin-derived T cells, by investigating sufficient numbers of individuals for statistical evaluation, and by correlating both in vivo and in vitro findings.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results Discussion References

 
Ni-allergic and nonallergic individuals

A total of 17 patients with a history of eczema and a positive epicutaneous patch test reaction to NiSO₄ and six healthy, nonallergic control individuals participated in this study after giving written consent. Patch tests were performed with 5% NiSO₄ in petrolatum and were evaluated after 48 and 72 h. All patients, but none of the control persons, showed a positive result. Positive reactions ranged from erythema with few papules to multiple papulovesicles (Table I). Lymphocyte proliferation assays were performed with PBMC immediately after patch testing. Skin biopsies were taken from six Ni-allergic patients and two nonallergic controls 24 h after performing an additional epicutaneous patch test with NiSO₄. This particular time point was chosen because the number of Ni-specific T cells in the cutaneous infiltrate decreases over time due to the secondary influx of bystander T cells of unrelated Ag specificity. Biopsies were placed in the culture media without prior mechanical disaggregation, leading to the emigration of the cutaneous T cells into the culture media. After 7–10 days of culture, 4–10 x 10⁶ skin-derived T cells were recovered from each 4-mm punch biopsy.

The following Ags were used in this study: NiSO₄ x 6 H₂O (20 µM), PdCl₂ (10 µM), CoCl₂ (1 µM), CuCl₂ (0.1–5 µM; all from Sigma-Aldrich, Deisenhofen, Germany), PHA (1%, Life Technologies, Rockville, MD), tetanus toxoid (TT³; 3.2 Lf/ml, Behring Diagnostics, Marburg, Germany). PBMC and patch test-derived T cells were cultured in RPMI 1640 (Life Technologies) supplemented with 2 mM L-glutamine, penicillin/streptomycin, 1 mM Na-pyruvate, 1x nonessential amino acids (all from Life Technologies), and 10% heat-inactivated pooled human AB serum (Sigma-Aldrich) or 10% FCS and 40 U/ml hIL-2 (Biotest Diagnostics, Dreieich, Germany), respectively.

Proliferative assays with peripheral and cutaneous T cells

PBMC were isolated from 20–40 ml of heparinized blood by density centrifugation on Lymphoflot (Biotest Diagnostics). Two 3x10⁵ PBMC were cultured in the presence or absence of Ag in 96-well round-bottom culture plates for 7 days (Falcon, Oxnard, CA). On day 6, triplicate microcultures were pulsed with 1 µCi/well [³H]thymidine (DuPont Pharmaceuticals, Mechelen, Belgium) and were harvested on GF/A filters after 18 h of incubation, and the incorporation of [³H]thymidine was measured in an automatic beta-counter (Wallac, Freiburg, Germany).

Patch test-derived T cells from six allergic and two nonallergic individuals were obtained as previously described (12). In short, punch biopsies from epicutaneous patch test reactions to NiSO₄ were cultured in RPMI 1640/10% FCS supplemented with 40 U/ml IL-2 in 24-well culture plates (Falcon) for 14 days. A total of 10⁵ in vitro-expanded cutaneous T cells were stimulated with 20 µM NiSO₄ and 2 x 10⁵ x-irradiated (5000 rad) autologous PBMC as APC in round-bottom microculture plates (Falcon). After 4 days, NiSO₄-specific proliferation was determined by the uptake of [³H]thymidine, which was added for 18 h. In some experiments, Ag-specific T cell proliferation was expressed as a stimulation index (SI), which is the ratio of [³H]thymidine uptake (cpm) in cultures with Ag and without Ag. A SI of 3 was considered to represent a significant proliferative response.

Cytokine secretion of NiSO₄-reactive skin-derived T cells

Cytokine secretion of cutaneous NiSO₄-reactive T cells was determined by coculture of 10⁵ T cells with 2 x 10⁵ x-irradiated (5000 rad) autologous PBMC as APC and Ag (NiSO₄, PdCl₂, CoCl₂, and CuCl₂). After 48 h, culture supernatants were collected and analyzed for IL-5, IL-10, and IFN- immunoreactivity by ELISA (Beckmann, Hamburg, Germany) according to the manufacturer’s instructions.

TCR-V usage of peripheral and cutaneous T cells

Analysis of the TCR-V repertoire of peripheral and cutaneous NiSO₄-reactive T cells was performed 7–10 days (PBMC) or 4 days (cutaneous T cells) after in vitro stimulation of the T cells with NiSO₄ or TT as a control Ag. For phenotypical analysis, 5 x 10⁴ T cells were resuspended in a staining buffer consisting of PBS supplemented with 3% FCS and 0.1% Na-azide (Sigma-Aldrich) and were incubated with mouse anti-human TCR-V mAb diluted at 1/10 for 30 min. The following mAb specific for TCR-V elements were used: (TCRBV)1S1, (TCRBV)2S1, (TCRBV)3S1, (TCRBV)5S1, (TCRBV)5S2, (TCRBV)5S3, (TCRBV)7S1, (TCRBV)8S1/S2, (TCRBV)V9S1, (TCRBV)11S1, (TCRBV)12S2, (TCRBV)13S1, (TCRBV)13S6, (TCRBV)14S1, (TCRBV)V16S1, (TCRBV)17S1, (TCRBV)18S1, (TCRBV)V20S1, (TCRBV)21S3, (TCRBV)22S1, and (TCRBV)23S1 (all from Immunotech, Hamburg, Germany). Following two washes with staining buffer, the cells were resuspended in staining buffer and incubated with a PE-labeled second Ab (PE rat anti-mouse IgG; Immunotech) for 30 min. After blocking with pooled mouse IgG (1 mg/ml; Sigma-Aldrich), PBMC were stained with a FITC-labeled anti-CD3 mAb (BD Biosciences, San Jose, CA). Following an additional washing step, cells were resuspended in staining buffer, and 5 x 10³ CD3⁺ T cells were analyzed on a FACScan flow cytometer (BD Biosciences) using a gate for lymphocytes.

Immunohistochemical analysis of the T cell infiltrate in epicutaneous patch test reactions to NiSO₄

Cryostat sections were prepared from skin biopsies 24 h after epicutaneous application of 5% NiSO₄. Skin sections were fixed in ice-cold acetone for 10 min and were then incubated with mAb specific for various TCR-V (diluted at 1/20) and anti-CD3, anti-CD4, and anti-CD8 mAb (diluted at 1/50; all from DAKO, Hamburg, Germany). mAbs were diluted in PBS/Tween/BSA and were added to each skin section in a volume of 100 µl for 30 min at room temperature. Skin sections were washed three times in PBS/Tween for 5 min and were then incubated with a second, AP-conjugated Ab (rat anti-mouse IgG; DAKO) at 1/100 in PBS/Tween/BSA for 30 min. After three washes with PBS/Tween/BSA, an APAAP-complex solution (DAKO; 1/100 in PBS/Tween/BSA) was added to each skin section for 30 min. Unbound complex was removed by three washes with PBS/Tween/BSA and skin sections were stained with fuchsin solution (DAKO). Skin sections were counterstained with hematoxylin for 2 min and were mounted with glycerol.

Statistical analysis

Peripheral T cells of the Ni-allergic donors expressing different TCR-V chains showed a differential proliferative response upon in vitro stimulation with NiSO₄ and TT, respectively. Accordingly, results of TCR-V usage are shown as box plots with medians and corresponding confidence intervals (Fig. 1A). Differences in TCR-V frequencies of Ni- and TT-stimulated peripheral T cells were tested pairwise for statistical significance by Wilcoxon test. To control for serial testing, a sequential Bonferroni adjustment (13) with a table-wide significance level of 0.1 was applied. Overexpression of distinct TCR-V chains of Ni-responsive peripheral T cells was further analyzed for a correlation with the extent of the proliferative PBMC response to NiSO₄ (SI) by a Spearman rank correlation analysis (Fig. 1B).

View larger version (23K): [in this window] [in a new window]   FIGURE 1. A, Preferential usage of restricted TCR-V chains by peripheral NiSO4-responsive T cells. NiSO4-responsive PBMC from 10 Ni-allergic donors (Table I) were either cocultured with NiSO4 () or TT as a control Ag () for 7 days and were stained with mAb against various TCR-V followed by a second, PE-conjugated Ab. Afterward, PBMC were stained with a FITC-conjugated anti-CD3 mAb. TCR-V expression of peripheral CD3+ T cells was finally determined by FACS analysis (double green/red fluorescence). The number of PBMC samples that were subjected to TCR-V analysis is given on the right of each plot (n). Median, vertical line; 25th and 75th percentiles, box; 5th and 95th percentiles, horizontal lines. Values of p derived from Wilcoxon tests are listed in the right column; significant differences after Bonferroni adjustment are printed in bold letters. B, TCR-V17 expression of peripheral T cells of 17 Ni-allergic donors correlates with their proliferative response to NiSO4. The proliferative in vitro response to NiSO4 of PBMC of 17 Ni-allergic donors, which is expressed as an SI (data shown in Table I), is plotted against the percentage of TCR-V17+ PBMC upon in vitro stimulation with NiSO4.

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

All 17 Ni-allergic donors studied showed positive patch test reactions of variable intensity to epicutaneously applied NiSO₄. Eleven of these individuals additionally showed a significant and reproducible peripheral T cell response to NiSO₄ while six of 17 donors showed only suboptimal or marginal proliferative T cell responses to NiSO₄ (Table I). Two donors showed also positive patch test reactivity to CoCl₂ and one to PdCl₂; PBMC from two donors developed a proliferative response to CoCl₂.

None of the six healthy controls showed a positive patch test reaction to NiSO₄ or a significant proliferative response of PBMC cultured with NiSO₄.

TCR-V17 is preferentially used by NiSO₄-reactive peripheral T cells

PBMC from 10 Ni-allergic donors (Table I) showed overexpression of TCR-V1, 3, 7, 8, 9, 12, 17, 21, and 23 upon stimulation with NiSO₄ as compared with stimulation with TT (Wilcoxon test, p < 0.05). Bonferroni adjustment for serial testing identified a more restricted preferential usage of the TCR-V elements 12, 17, and 21 by the NiSO₄ responsive T cells (Fig. 1A). A Spearman rank correlation analysis with data of all 17 Ni-allergic donors revealed a significant relationship of TCR-V17 but neither of TCR-V12 (rs = -0.277, p > 0.1) nor of TCR-V21 (rs = 0.063, p > 0.1) frequencies with the extent of NiSO₄-induced T cell proliferation (Fig. 1B). This correlation was still significant when the values of donor M34 were excluded from the analysis. Peripheral T cells of the two donors M34 (Fig. 2) and M52 with severe Ni-induced contact dermatitis showed a >10-fold increase of TCR-V17 expression after stimulation with NiSO₄ compared with stimulation with TT (M34: Ni, 14.11% and TT, 1.1%; M52: Ni, 6.9% and TT, 0.6%; percentages related to total CD3⁺ cells). In contrast, there was no comparable increase of TCR-V12 (M34, 1.3%; M52, 0.7%) or V21 (M34, 2.0%; M52, 0.5%) usage by peripheral T cells from these donors upon in vitro stimulation with NiSO₄.

View larger version (34K): [in this window] [in a new window]   FIGURE 2. Preferential usage of TCR-V17 by peripheral T cells of donor M34 with severe Ni-induced contact dermatitis. PBMC from donor M34 with strong epicutaneous patch test reaction to NiSO4 (Table I) were cocultured with NiSO4 or TT and were stained with mAb against various TCR V followed by a second, PE-conjugated Ab. Afterward, PBMC were stained with a FITC-conjugated anti-CD3 mAb, and TCR-V expression of CD3+ T cells was determined by FACS analysis (double green/red fluorescence).

TCR-V17⁺ T cells are a major component of the T cell infiltrate in NiSO₄-induced contact dermatitis

Histological examination of skin sections of five Ni-allergics (M26, M27, M38, M42, and M52) with Ni-induced contact dermatitis showed a cellular infiltrate, which was primarily composed of CD3/CD4⁺ T cells (Fig. 3). In all these patients, the cutaneous CD3⁺ T cell infiltrate contained a high proportion of TCR-V17⁺ T cells (Fig. 3). In contrast, TCR-V12 and V21 (which were also expressed by peripheral T cells) were only occasionally detected on the cutaneous T cell infiltrate in Ni-induced contact dermatitis (not shown). In addition, TCR-V2, which is overexpressed by T cells in normal human skin, was rarely detected in the cutaneous T cell infiltrate in the Ni-allergic donors (Fig. 3). Biopsies of patch tests with NiSO₄ from the two nonallergic control donors Co1 (Fig. 3) and Co2 (not shown) contained only a sparse T cell infiltrate that did not express TCR-V17.

View larger version (68K): [in this window] [in a new window]   FIGURE 3. The majority of cutaneous T cells in NiSO4-induced contact dermatitis express TCR-V17. Skin biopsies were taken from five Ni-allergic donors (M26, M27, M38, M42, and M52) and a nonallergic donor (Co1) 24 h after epicutaneous application of NiSO4. Cryostat sections of the biopsies were stained with mAb against human CD4 and against various TCR-V. Skin sections were then incubated with a second, AP-conjugated Ab followed by a final incubation with APAAP-complex solution. Shown is the expression of CD4, TCR-V17, and TCR-V2 of the cutaneous T cell infiltrate.

NiSO₄-responsive cutaneous T cells preferentially express TCR-V17

T cells derived from patch tests with NiSO₄ of four of six Ni-allergic donors developed a vigorous proliferative in vitro response to NiSO₄ (Table II). In contrast, patch test-derived T cells from the two Ni-allergic donors, M26 and M27, and from the nonallergic controls, Co1 and Co2, were not responsive to NiSO₄ (Table II). To address the question of whether T cell responsiveness to NiSO₄ correlated with the expression of TCR-V17, the cutaneous T cells were double stained with mAb against CD3 and various TCR-V chains. In fact, the Ni-responsive cutaneous T cell lines from donors M38, 42, and 52 preferentially used TCR-V17, whereas the Ni-unresponsive cutaneous T cells from donors M26, M27, Co1, and Co2 (not shown) did not express TCR-V17 (Fig. 4). TCR-V12 and V21 were only expressed by a minor fraction of the cutaneous T cells from NiSO₄-induced patch test reactions (Fig. 4), which is consistent with the low frequency of V12⁺ and V21⁺ T cells found in NiSO₄-induced contact dermatitis in vivo. Thus, these findings strongly suggest that Ni responsiveness of cutaneous T cells correlates with the expression of TCR-V17.

View larger version (40K): [in this window] [in a new window]   FIGURE 4. Disparate in vitro responsiveness to NiSO4 of TCR V17+ and TCR-V17- cutaneous T cells. Skin-derived T cells were subjected to analysis of TCR-V expression by FACS after in vitro stimulation with NiSO4. Cutaneous T cells from donors M38, M42, and M52 that showed a vigorous proliferative response to NiSO4 (Table II) showed a preferential expression of TCR-V17. In contrast, patch test-derived T cells from donors M26 and M27 and the nonallergic control Co1 that were unresponsive to NiSO4 (Table II) showed marginal or no expression of TCR-V17.

Cutaneous T cells from four Ni-allergic donors showed a vigorous proliferative in vitro response to NiSO₄ (Table II). Skin-derived T cells from the three Ni-allergic donors, M38, M42, and M52, that showed an increased expression of TCR-V17 (Fig. 4) were strongly stimulated by NiSO₄ and to a lesser extent by PdCl₂ (M38 and M42) and by CoCl₂ (M42; Fig. 5). NiSO₄-specific cutaneous T cells of donors M38, M42, and M46 produced substantial amounts of IL-5 but no IFN- or IL-10 upon stimulation with NiSO₄, suggesting a Th2 cytokine profile. In contrast, upon Ag-independent stimulation with PHA, they produced both IL-5 and IFN- (Fig. 5).

View larger version (42K): [in this window] [in a new window]   FIGURE 5. NiSO4-responsive cutaneous T cells secrete a Th2-type cytokine pattern. Cutaneous Ni-reactive T cells of the Ni-allergic donors M38, M42, and M46 were cocultured with autologous, x-irradiated PBMC as APC and NiSO4, PdCl2, CuCl2, and CoCl2 for 4 days, and the proliferative response was determined by the uptake of [3H]thymidine. Cytokine (IFN- and IL-5) analysis was performed in supernatants from cultures with significant T cell responses to Ag.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

Several independent investigations have tried to define the structural diversity of the TCR of Ni-specific peripheral and cutaneous T cells. Zollner et al. (10) investigated a cohort of 10 Ni-allergic individuals. Similarly to the present study, PBMC from the donors were cocultured with NiSO₄ and IL-2 for 10 days before phenotypical analysis with mAb against 11 distinct TCR-V chains. Ni-responsive PBMC from two of 10 Ni-allergic donors showed an increased usage of V2, and Ni-responsive PBMC from three additional Ni-allergic individuals showed a preferential usage of either V17, V18, or V21.3 upon in vitro culture with NiSO₄/IL-2 compared with culture with IL-2 alone. Immunohistochemical analysis of NiSO₄-induced patch test reactions revealed a significant under-representation of TCR-V2 and V3 and an over-representation of V8 in skin-derived compared with blood-derived T cells from these Ni-allergic donors (10). Because skin biopsies in their study were taken 72 h after epicutaneous NiSO₄ challenge (in contrast to 24 h in this study), the cutaneous infiltrate may have contained substantial numbers of bystander cells of unrelated specificity. Werfel et al. (8) investigated the TCR repertoire of a panel of blood- and skin-derived CD4⁺ Ni-reactive T cell clones from two Ni-allergic donors. Their findings suggested a less restricted usage of TCR-V chains by NiSO₄-responsive T cells. Of 79 blood- and skin-derived Ni-reactive T cell clones, 40% expressed the TCR elements V2, V6.7/V14, V13.1/13.2, and V20. In a more recent study, peripheral T cells from three donors with severe Ni allergy showed an impressive over-representation of the TCR-V17 element (12–16%) upon in vitro stimulation with NiSO₄ (9). Moreover, the authors showed that TCR-V17 expression correlated with the clinical severity of Ni-induced contact dermatitis. This finding is in line with and is extended by the present study showing that TCR-V17 is overexpressed by both peripheral and cutaneous Ni-responsive T cells and correlates with the clinical severity of Ni-induced contact dermatitis and the proliferative T cell response to NiSO₄.

In this study, TCR other than V17 were not consistently overexpressed by skin-derived Ni-responsive T cells. In particular, TCR-V2, which was previously identified to be preferentially used by peripheral (10) and cutaneous (8) T cells of selected Ni-allergic donors, was neither overexpressed by peripheral nor by cutaneous Ni-responsive T cells. There is a bias toward expression of TCR-V2 by peripheral T cells in healthy individuals (14), as well as a preferential usage of V2 and V6 by cutaneous T cells in normal skin (15).

In addition to TCR-V17, TCR-V12 and TCR-V21 that were found to be preferentially used by peripheral Ni-reactive T cells in this study were not overexpressed in vivo and in vitro by cutaneous T cells in NiSO₄-induced contact dermatitis. This finding is in line with the aforementioned previous studies that did not consistently detect an overexpression of TCR-V12 or V21 by peripheral or cutaneous Ni-responsive T cells (8, 9, 10).

The Ni-responsive cutaneous T cells produced the Th2 cytokine, IL-5, but no IFN- and IL-10 upon stimulation with Ni, which is consistent with the previous identification of Ni-responsive cutaneous Th2 cells in Ni-induced contact dermatitis (8, 16). A recent study suggested that Ni-reactive peripheral T cells also belonged to the Th2 type because they produced more IL-4 and IL-5 than peripheral T cells from nonallergic donors (17). The preferential detection of cutaneous Th2 cells in Ni hypersensitivity (8, 16) suggests a role for these cells in the effector phase of Ni contact dermatitis, although their biological function still remains to be elucidated. However, there is evidence that Ni hypersensitivity is also associated with the presence of Ni-reactive Th1 cells (18). Cavani et al. (19) identified both Ni-responsive CD8⁺ and CD4⁺ T cells in the blood of Ni-allergic donors, whereas nonallergic individuals had only Ni-responsive peripheral CD4⁺ T cells. Both CD4⁺ and CD8⁺ may be critical in Ni-induced contact dermatitis as demonstrated in murine models of contact sensitivity (20, 21). Human Ni-reactive CD8⁺ T cells displayed cytotoxicity against Ni-pulsed epidermal keratinocytes and may thus contribute to the pathology of Ni-induced contact dermatitis (22, 23). Ni-responsive CD4⁺ Th1 cells are also potentially cytotoxic against keratinocytes, whereas Ni-reactive Th2 cells are not (19). Moreover, IL-10-secreting CD4⁺ T regulatory cells seem to be involved in the regulation of Ni-induced contact dermatitis by inhibiting the maturation of dendritic cells (24). Thus, Ni allergy represents a unique paradigm of human allergic contact dermatitis with many solved questions regarding the pathogenic role that T cells play in hapten-induced contact sensitivity (25).

In summary, Ni hypersensitivity may be considered a T cell-mediated immune response characterized by the preferential usage of a restricted TCR-V repertoire involved in Ag recognition. Vollmer et al. (26, 27) demonstrated that Ni activates TCR-V17⁺ T cells in a nonsuperantigen-like manner because specific combinations of TCR - and -chains were required for proper T cell activation. In addition, mutations of the complementarity-determining region 3 of TCR-V17 (the site of the TCR that presumably interacts with peptide bound to MHC) abrogated T cell recognition of NiSO₄ (26). Pd²⁺, a bivalent metal ion closely related to Ni²⁺, seems to exhibit similar conformation because the Ni-responsive cutaneous T cells were also stimulated by Pd. This observation is also consistent with previous observations showing that Ni-reactive T cell clones frequently cross-react with Pd and Cu (28, 29). Thus, Ni-induced contact dermatitis holds great promise as a model system to establish therapeutic concepts to specifically modulate hypersensitivity reactions to haptens such as various ubiquitous and occupational allergens, including metals, contact sensitizers, drugs, etc. Evidence for the general feasibility of this approach has been provided by Preckel et al. (30) who identified altered hapten ligands that antagonized hapten-specific cytotoxic T cells.

	Acknowledgments

 
We thank Sybille Thoma-Uszynski for critical review of the manuscript.

	Footnotes

 
¹ This study was supported by a grant from the Interdisciplinary Center for Clinical Research of the Rheinisch-Westfälische Hochschule (to L.B.) and by the Deutsche Forschungsgemeinschaft (He 1602/5-2 to M.H.).

² Address correspondence and reprint requests to Dr. Michael Hertl, Department of Dermatology, University of Erlangen, Hartmannstrasse 14, D-91054 Erlangen, Germany. E-mail address: Michael.hertl{at}derma.med.uni-erlangen.de

³ Abbreviations used in this paper: TT, tetanus toxoid; SI, stimulation index.

Received for publication May 18, 2001. Accepted for publication September 13, 2001.

	References

Top Abstract Introduction Materials and Methods Results Discussion References

 

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