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. 2005 Jul;141(1):107–115. doi: 10.1111/j.1365-2249.2005.02823.x

Interleukin-4 induced down-regulation of skin homing receptor expression by human viral-specific CD8+ T cells may contribute to atopic risk of cutaneous infection

S L Seneviratne *, L Jones *, A S Bailey *, R V Samuel *, A P Black *, G S Ogg *,†
PMCID: PMC1809403  PMID: 15958076

Abstract

Factors controlling the expression of cutaneous lymphocyte-associated antigen (CLA) by T cells are poorly understood, but data from murine and human CD4+ T cell systems have suggested that cytokines play an important role. However, there are no data examining the influence of cytokines on the expression of CLA by human antigen-specific CD8+ T cells. Peripheral blood mononuclear cells (PBMC) were isolated from 10 HLA-A*0201-positive healthy individuals. Using HLA-peptide tetrameric complexes refolded with immunodominant peptides from Epstein—Barr virus (EBV), cytomegalovirus (CMV) and influenza A virus, we investigated the temporal associations of CLA expression by viral-specific CD8+ T cells following stimulation with antigen. Ex vivo influenza matrix-specific CD8+ T cells expressed significantly (P < 0·05) greater levels of CLA than EBV BMLF1 and CMV pp65-specific CD8+ T cells (mean 9·7% influenza matrix versus 1·4% BMLF1 versus 1·1% pp65) and these differences were sustained on culture. However, regardless of viral specificity, interleukin (IL)-12 and IL-4 induced significant (P < 0·05) dose-dependent up-regulation and down-regulation of CLA expression, respectively, with IL-4 showing a dominant negative effect. In many cases, IL-4 resulted in complete abrogation of detectable CLA expression by the viral-specific CD8+ T cells. Overall these data demonstrate that CLA expression by human viral-specific CD8+ T cells is highly dynamic and that IL-4 causes significant down-regulation. Disorders associated with a type 2 cytokine shift may reduce the efficiency of skin homing by viral-specific CD8+ T cells. Furthermore, the ability to modify the local and systemic microenvironment may offer novel therapeutic strategies that influence tissue-specific T cell homing.

Keywords: CD8+ T cells, CLA, IL-4, IL-12

Introduction

Controlled expression of vascular selectins and their ligands is thought to be essential in the regulated recruitment of T lymphocytes to lymphoid tissue and sites of inflammation. The cutaneous lymphocyte-associated antigen (CLA) is predominantly a carbohydrate modified form of P-selectin glycoprotein ligand-1 and is believed to be a marker of cells that can interact with E-selectin [1–3]. The latter is expressed on venular endothelial cells of inflamed skin, oral mucosa and the female genital tract, and provides the initial signals that trigger rolling of CLA-positive T cells along endothelium. While the degree of CLA expression by T cells correlates with adhesion to E selectin and shear stress resistance under hydrodynamic conditions [4], there is evidence suggesting that other ligands have E selectin binding activity [2,5–10]. CLA is expressed by the majority of T cells within cutaneous inflammatory infiltrates, but is expressed by only 5–20% of peripheral blood T cells. The frequency of peripheral blood T cell expression of CLA is typically raised in individuals with diverse inflammatory and malignant skin diseases including atopic dermatitis, psoriasis, vitiligo and cutaneous T cell lymphoma; and indeed may correlate with disease severity [11–14]. These findings are consistent with a relevant role for CLA in the recruitment of T cells to sites of cutaneous inflammation.

Expression of leucocyte α1,3-fucosyltransferase-VII (FucT-VII) is a key regulatory step in the generation of functional ligands for E-selectin, through the addition of fucose residues to sialylated lactosamine precursors in an α1,3-linkage [15]. Such carbohydrate modification of the P-selectin glycoprotein ligand-1 backbone confers reactivity with the HECA-452 monoclonal antibody, a marker for CLA-positive cells. HECA-452 may also recognize HCELL (haematopoietic cell E-/l-selectin ligand), a N-linked glycoform of CD44 associated with E-selectin binding activity on haematopoetic stem cells [8–10], and there may be other E-selectin binding structures. The regulation of FucT-VII expression is relatively poorly understood but is thought to be influenced by a number of cytokines, including interleukin (IL)-12, transforming growth factor (TGF)-β, IL-10 and IL-4 [16–21], which in turn influence the expression of cell surface CLA. Several other factors have also been observed to affect CLA expression including dendritic cell immunization route [22], antigen site [23,24], superantigen [25] and serum [4]; and indeed such factors may alter the efficacy of the subsequent immune response [26]. Therefore the expression of CLA shows remarkable plasticity and is likely to be strongly influenced by the local and systemic cytokine environment. While these data provide broad insights to the effects of cytokines on CLA expression, there have been no data on the influence of cytokines on human CD8+ T cells specific for particular antigens.

The expression of CLA associates with a number of cell surface and functional markers in addition to the binding to E selectin. CLA positive cells are more likely to express T cell activation and differentiation markers putatively linked to antigen experience such as CD45RO+, CD45RA− and HLA-DR [16]. Other studies have suggested that CD62L and CCR7 [27–29] may be co-expressed with CLA in a significant number of peripheral blood T cells. CLA-positive cells are also more likely to express CCR4 and CCR10, chemokine receptors that may play a role in chemotaxis to inflamed epidermis via TARC/CCL17 and CTACK/CCL27, respectively [30–36]. Overall these data would be consistent with the up-regulation of CLA expression on antigen encounter and differentiation towards a central memory or effector memory phenotype. Furthermore, it is clear that CLA-positive T cells are able to produce both type 1 and type 2 cytokines under different conditions.

Few studies have addressed the expression of CLA by T cells specific for particular antigens. In the first such study, high frequencies of CLA-positive functional MelanA-specific CD8+ T cells were identified in the peripheral blood of individuals with vitiligo, consistent with a role for CD8+ T cells in the pathogenesis of melanocyte destruction [11]. House dust mite-derived Der p 1-specific CD8+ T cells have been observed in the blood of individuals with atopic disease and approximately 50% of the antigen-specific cells expressed CLA [37]. Herpes simplex virus (type II)-specific CD8+ T cells express high levels of CLA, which is consistent with their specificity for a skin-tropic virus [28]. There are no data on the influence of cytokines on CLA expression by antigen-specific T cells.

We sought to test the hypothesis that cytokines could influence CLA expression by human CD8+ T cells specific for three common viruses. We observed that basal levels of CLA expression differ between CD8+ T cells with different viral specificities, but that all demonstrate significant changes on exposure to cytokines. Significant up-regulation was observed with IL-12 and significant down-regulation was observed with IL-4. In environments associated with type 2 cytokine production such as atopic dermatitis, the IL-4-induced down-regulation of CLA by viral-specific CD8+ T cells may contribute to the relative susceptibility to cutaneous viral infections.

Materials and methods

Subjects

Ten healthy HLA-A*0201-positive [based on sequence-specific polymerase chain reaction (PCR)] individuals and five HLA-A*0201-positive individuals with atopic disease were recruited under ethical approval from the Oxfordshire Clinical Research Ethics Committee.

Antigen-specific T cell culture

Peripheral blood mononuclear cells (PBMC) were centrifuged for 5 min at 300 g and the supernatant removed; 100 µl of 200 µ M filtered peptide was added and the cells incubated for 1 h at 37°C/5%CO2. The cells were resuspended in R10 (RPMI-1640 medium (Gibco BRL, Paisley, UK) supplemented with 10% fetal calf serum (FCS) (Globepharm Ltd, Guildford, Surrey, UK), 2 mMl-glutamine, 50 U/ml penicillin and 50 µg/ml streptomycin) medium with IL-7 (25 ng/ml) into 24-well plates at 2 × 106 cells/ml. On day 4, IL-2 was added to a final concentration of 50 IU/ml. Peptides used for T cell culture and for synthesizing MHC—peptide tetrameric complexes were synthesized at the laboratory in-house facility on an automated peptide synthesiser (396 MPS, Advanced Chemtech, Cambridge, UK) by conventional solid phase Fmoc chemistry. These peptides were all analysed for purity by reverse-phase high-perfomance liquid chromatography (HPLC). Cells were grown at 37°C with 5% CO2 in R10 medium, unless otherwise stated. Cell lines were regularly screened for mycoplasma infection.

HLA-peptide tetrameric complexes

HLA-peptide tetrameric complexes (tetramers) were synthesized as described previously [38,39]. Purified HLA heavy chain and β2 microglobulin were synthesized by means of a prokaryotic expression system (pET Novagen, Nottingham, UK). The heavy chain was modified by deletion of the transmembrane/cytosolic domain and C-terminal addition of a sequence containing the BirA enzymatic biotinylation site. Heavy chain, β2 microglobulin and peptide were refolded by dilution. The following nine amino acid peptide epitopes were used: Epstein—Barr virus (EBV) BMLF1280—8 GLCTLVAML, cytomegalovirus (CMV) pp65 495–503 NLVPMVATV and influenza matrix 58–66 GILGFVFTL. The 45 kDa refolded product was isolated by fast protein liquid chromatography (FPLC), and then biotinylated by BirA (Avidity, CO, USA) in the presence of biotin (Sigma, Poole, UK), ATP (Sigma) and Mg2+ (Sigma). Streptavidin—phycoerythrin conjugate (Sigma) was added in a 1 : 4 molar ratio and the tetrameric product was concentrated to 1 mg/ml.

Flow cytometry

Four-colour flow cytometric analysis was performed using a FACSCalibur (Becton Dickinson, Oxford, UK) with CellQuest software (Becton Dickinson). PBMC, 106, were centrifuged at 300 g for 5 min and resuspended in a volume of 50 µl. Tetrameric complex was added and incubated at 37°C for 20 min. Directly conjugated antibodies [including anti-CD8 peridinin chlorophyll (PerCP), anti-CD45RO-APC (Becton Dickinson); anti-CLA-FITC, anti-CD45RA PE (BD Pharmingen, Oxford, UK)] were added according to the manufacturers’ instructions, and the samples incubated for 60 min at 4°C. After two washes in cold phosphate-buffered saline (PBS) the samples were fixed in 2% formaldehyde. Specific controls used were PBMC from HLA-A*0201-negative individuals. In line with previous reports, the mean ± 3 standard deviations (s.d.) of tetramer-binding cells in the PBMC from all control individuals was less than 0·02% of CD8+ T cells.

Statistics

Statistical analyses were performed using non-parametric t-tests and Pearson correlation coefficient.

Results

CLA expression by viral-specific CD8+ T cells ex vivo

As shown in Table 1, the percentage of CD8+ T cells binding each tetramer directly ex vivo were 0–1·2% (mean 0·49%) BMLF1, 0–1·2% (mean 0·42%) pp65, 0–0·3% (mean 0·11%) influenza matrix. The proportion of individuals with detectable tetramer binding cells ex vivo were 90% BMLF1, 60% pp65 and 70% influenza matrix. We did not identify herpes simplex virus type II-specific CD8+ T cells ex vivo in our cohort. Of those with detectable cells the percentage expressing CLA is shown in Table 2. The levels of CLA expression by the influenza matrix-specific CD8+ T cells were significantly greater than those expressed by the BMLF1 and pp65-specific CD8+ T cells [mean 9·7% influenza matrix, 1·4% BMLF1 (P < 0·05), 1·1% pp65 (P < 0·05)]. Figure 1 shows an example of tetramer co-staining with anti-CLA for each of the three tetramers and illustrates that levels of CLA expression by both CMV pp65 and EBV BMLF1-specific CD8+ T cells is barely detectable ex vivo.

Table 1. Frequencies of Epstein—Barr virus (EBV) BMLF1, cytomegalovirus (CMV) pp65 and influenza matrix-specific CD8+ T cells (as a percentage of total CD8+ T cells) when peripheral blood mononuclear cells (PBMC) from 10 healthy subjects S1—S10 were stained direct ex vivo using viral peptide-major histocompatibility complex (MHC) class I tetrameric complexes (a dash represents that they had no detectable tetramer staining).

Subject HLA type EBV CMV Influenza
S1 A*0201 0·8 0·7 0·2
S2 A*0201 1·2 – 0·12
S3 A*0201 1·1 1·0 0·3
S4 A*0201 0·7 0·3 0·1
S5 A*0201 0·1 0·2 –
S6 A*0201 – 1·2 –
S7 A*0201 0·4 – 0·05
S8 A*0201 0·3 – –
S9 A*0201 0·2 – 0·14
S10 A*0201 0·1 0·8 0·2
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Table 2. Mean (s.d.) percentage of Epstein—Barr virus (EBV), cytomegalovirus (CMV) and influenza-specific CD8+ T cells that express lymphocyte-associated antigen (CLA), CD62L and CCR7 when peripheral blood mononuclear cells (PBMCs) are stained direct ex vivo.

EBV CMV Influenza
CLA  1·4 (0·4) 1·1 (0·3)  9·7 (4·1)
CD62L  7·6 (1·8) 4·8 (1·0)  8·1 (1·9)
CCR7 15·8 (2·8) 8·8 (2·3) 17·3 (3·5)
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Fig. 1.

Fig. 1

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Representative figure showing the expression of the lymphocyte-associated antigen (CLA) on Epstein—Barr virus (EBV) BMLF1, cytomegalovirus (CMV) pp65 and influenza matrix-specific CD8+ T cells when tested direct ex vivo. The figure in the right upper quadrant represents the percentage of EBV, CMV or influenza tetramer positive cells that also express CLA.

The levels of CD62L and CCR7 were not significantly different between EBV BMLF1 and influenza matrix-specific CD8+ T cells, but were significantly lower for the CMV pp65-specific CD8+ T cells (P < 0·05 for BMLF1 versus CMV and influenza matrix versus CMV). These findings confirm previous data on the expression of phenotypic markers by CMV pp65-specific CD8+ T cells [40,41].

CLA expression by cultured viral-specific CD8+ T cells

Antigen-specific CD8+ T cell lines were generated using peptide-pulsed PBMC with IL-2 and analysed at days 5, 7, 10 and 14 for the presence of tetramer-binding cells. The addition of 25 ng/ml IL-7 significantly (P < 0·01) increased the number of antigen-specific CD8+ T cells, but did not alter the expression of CLA. After 14 days of culture, 10–60% of the CD8+ T cells within the cultures were able to bind tetramer, but the frequency of such tetramer-binding cells did not correlate with the expression of CLA. Although there were significant differences between CLA expression ex vivo and after culture, there were no significant differences between days 5, 7, 10 and 14, suggesting that the maximal changes had become established by day 5. We were unable to analyse for tetramer binding prior to day 5 due to the known antigen-induced T cell receptor down-regulation that occurs at establishment of the lines and which takes several days to recover. The mean proportion of tetramer-binding cells that expressed CLA at day 5 was 3·9% EBV BMLF1, 4·5% CMV pp65 and 55% influenza matrix. The proportion of influenza matrix-specific CD8+ cells that were positive for CLA were significantly (P < 0·01) greater than the proportions for both EBV BMLF1 and CMV pp65. Figure 2 shows examples of anti-CLA and tetramer co-staining of cultured viral-specific T cell lines and confirms that influenza matrix-specific CD8+ T cells express higher levels of CLA than EBV BMLF1 and CMV pp65-specific CD8+ T cells ex vivo and after culture with antigen. There were no significant changes in CD62L expression by the viral-specific CD8+ T cells in the presence of IL2 and IL-7. The proportional increase in CLA expression by the tetramer-binding cells was significantly greater than for the non-tetramer-binding CD8+ T cells, suggesting that T cell activation (for example, by antigen) is an important co-factor in the induction of CLA.

Fig. 2.

Fig. 2

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Figure representing the percentage of Epstein—Barr virus (EBV) BMLF1, cytomegalovirus (CMV) pp65 and influenza matrix-specific CD8+ T cells expressing lymphocyte-associated antigen (CLA) when cultured using interleukin (IL)-2 + IL-7. The figure in the right upper quadrant represents the percentage of EBV, CMV or influenza tetramer positive cells that also express CLA.

Influence of IL-4 and IL-12 on CLA expression by viral-specific CD8+ T cells

IL-4 and IL-12 have been shown to alter CLA expression by CD4+ T cells via the inhibition and induction of Fuc T-VII, respectively [17,20]; however, this has not been documented in the setting of human antigen-specific CD8+ T cells. Figure 3 shows the influence of 5 ng/ml IL-4 and 5 ng/ml IL-12 on CLA expression by influenza matrix and EBV BMLF1-specific CD8+ T cells at day 5 after antigen stimulation. IL-4 induced a significant (P < 0·05) down-regulation of CLA expression by the viral-specific CD8+ T cells, while the IL-12 induced a significant (P < 0·05) up-regulation with virtually all the influenza matrix-specific CD8+ T cells expressing CLA. Similar findings were observed with the EBV BMLF1 and CMV pp65-specific CD8+ T cells suggesting that these cytokines influence CLA expression with little difference between viral specificities. The effects of the cytokines were often dramatic and dose—response curves showed effects down to 1 ng/ml (Fig. 4). Figure 4 also shows the influence of the combination of IL-4 and IL-12, with the former having a dominant negative effect with concentrations down to 1 ng/ml. IL-4 induced significant (P < 0·05) increases in both CD62L and CCR7 by the viral-specific CD8+ T cells but IL-12 showed no significant influence on CD62L and CCR7. There were no significant differences in the changes in CLA staining of tetramer-binding cells between those with atopic disease and healthy controls. These data show that IL-4 and IL-12 have profound broad influences on the expression of CLA and other homing receptor properties by antigen-specific CD8+ T cells despite differing viral specificity.

Fig. 3.

Fig. 3

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Expression of lymphocyte-associated antigen (CLA) on viral-specific CD8+ T cells in influenza matrix and BMLF1-specific cultures using either interleukin (IL)-2 + IL-7, IL-2 + IL-7 + IL-4 or IL-2 + IL-7 + IL-12 in the culture medium. The figure in the right upper quadrant represents the percentage of tetramer-positive cells that express CLA.

Fig. 4.

Fig. 4

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Percentage [mean (SD)] of Epstein—Barr virus (EBV) BMLF1-specific CD8+ tetramer-positive cells that express lymphocyte-associated antigen (CLA) with different concentrations of interleukin (IL)-12 alone (diamonds), IL-4 alone (squares) or IL-12 + IL-4 (triangles). In the absence of IL-4 and IL-12, the mean percentage of cultured EBV tetramer-binding cells that expressed CLA in the experiment was 4·1% (0·9). At all concentrations tested, the difference between the percentage of cells expressing CLA with IL-12 alone and IL-12/IL-4 combined was significant (P < 0·01).

Although the changes were not as marked as with IL-4 and IL-12, we nevertheless observed significant (P < 0·05) increases in CLA expression by viral-specific CD8+ T cells in response to 10 ng/ml of TGF-β, IL-15 and IL-10 but not IL-18. The mean (s.d., P-value) for the individual cytokines was as follows: TGF-β 9·7% (2·1, P < 0·05), IL-15 23·4% (4·9, P < 0·05), IL-10 21·3% (3·7, P < 0·05) and IL-18 3·8% (1·2, not significant). Figure 5a shows examples of staining with anti-CLA and the EBV BMLF1-tetramer on culture with the cytokines. Furthermore, we investigated whether other Th2 cytokines such as IL-5 and IL-13 could influence CLA expression by viral-specific CD8+ T cells. Figure 5b shows that IL-5 had no detectable effect on CLA expression at 10 ng/ml, but IL-13 induced significant down-regulation (P < 0·01) of CLA. However, the changes observed with IL-13 were not as marked as those observed in the presence of IL-4, with a mean of 50% of antigen-specific CD8+ T cells losing CLA expression with IL-13. These data show that regardless of viral specificity, the expression of CLA by human CD8+ T cells can be dramatically influenced by the local cytokine conditions.

Fig. 5.

Fig. 5

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Representative figures to show the effects in (a) of the cytokines transforming growth factor (TGF)-β, interleukin (IL)-8, IL-15 and IL-10 on expression of lymphocyte-associated antigen (CLA) on Epstein—Barr virus (EBV) BMLF1-specific CD8+ T cell cultures. (b) Influence of IL-5 and IL-13 on the expression of CLA by EBV BMLF1-specific CD8+ T cells in a separate experiment. The figure in the right upper quadrant represents the percentage of tetramer positive cells that express CLA.

Discussion

We have shown for the first time that CLA expression by human CD8+ T cells specific for a number of different viruses can be influenced by cytokines, with significant down-regulation by IL-4 and up-regulation by IL-12, IL-15, TGF-β and IL-10. Of these, the most dramatic changes were observed with IL-4 and IL-12, and the effects were seen regardless of viral specificity.

Influenza-specific CD8+ T cells showed greater basal ex vivo and induced levels of CLA expression than EBV BMLF1 and CMV pp65-specific CD8+ T cells. The basal levels of expression by the CMV and EBV-specific CD8+ T cells were similar to those reported previously [28,37], but CLA expression by influenza-specific CD8+ T cells has not been documented previously. It is possible that these differences relate to the initial sites of priming or to the cytokine milieu within one of the trafficking compartments through which the cells migrate. Basal CLA expression by herpes simplex type II-specific CD8+ T cells has been reported to be up to 80%[28], with mean levels of 40% for Der p 1-specific CD8+ T cells in atopics [37] and 80% of MelanA-specific CD8+ T cells in individuals with vitiligo [11]. Overall these findings suggest that influenza matrix-specific CD8+ T cells may contain a significant subset that is able to home preferentially to venular endothelium-expressing E selectin, such as inflamed skin or oral mucosa.

IL-4 showed a dominant negative effect on CLA expression by the viral-specific CD8+ T cells, frequently resulting in total loss of detectable CLA (Fig. 4). We have also observed that IL-4 shows a similar down-regulation of CLA expression by CD4+ T cells stimulated with staphylococcal enterotoxin B (data not shown). It may be possible, therefore, that disorders associated with a type 2 cytokine pattern could influence the skin homing efficiency of viral-specific CD8+ T cells. Indeed IL-4 knock-out mice have altered tissue-specific T cell homing [42]. Atopic dermatitis is a disorder often characterized by the presence of type 2 cytokines in the blood and skin, and is also associated with a relative susceptibility to cutaneous viral infections such as herpes simplex, human papillomavirus and molluscum contagiosum. In contrast, psoriasis is a disorder often associated with a dominant type 1 cytokine pattern and affected individuals show no increased susceptibility to these common cutaneous viruses, which may be explained at least in part by differences in innate immune response genes [43]. Clearly, skin homing by viral-specific CD8+ T cells is possible [28], but a relative reduction in skin homing efficiency in individuals with atopic dermatitis may contribute further to their risk of cutaneous viral infection. This would be supported by the observation that approximately 40% of Der p 1-specific CD8+ T cells express CLA in individuals with atopic dermatitis, compared to over 80% of viral-specific and auto-antigen-specific CD8+ T cells in non-atopics. Furthermore, it would also be supported by the observation that diverse forms of cutaneous antigen challenge can lead to systemic effects in the absence of cutaneous sequelae [44,45]. A relative reduction in skin homing efficacy may be sufficient to reduce the control of cutaneous viral replication.

IL-15 is produced by a number of cell types including PBMC, placenta, muscle, kidney and lung, with the dominant source believed to be monocytes and dendritic cells. The cytokine has diverse effects but the principle roles appear to be in the development, survival and activation of natural killer cells and the proliferation of T cells. Indeed, it is known that IL-15Ralpha−/− knock-out mice have defects in lymphocyte homing [46]. In the current study, IL-15 induced the expression of CLA on viral-specific CD8+ T cells confirming the close link between innate and adaptive immunity. In addition, both TGF-β and IL-10 induced significant expression of CLA by viral-specific CD8+ T cells. TGF-β has been shown previously to modify FucT-VII expression [18] but there are no data on the influence of IL-10. Both these cytokines have been associated putatively with different types of regulatory T cells, raising the possibility that modification of tissue specific homing properties may be a novel regulatory mechanism.

The ability to modify tissue-specific homing properties may represent a therapeutic strategy to influence the homing of pathogenic T cell subsets. Indeed, several inhibitors of CLA/E-selectin interactions have already been investigated [47–50]. The data in the current study suggest that the use of cytokines or cytokine inhibitors may provide alternative therapeutic strategies for T cell-mediated diseases associated with particular tissue specificity.

In summary, these data confirm that human CD8+ T cells with specificity for different viruses have differing levels of CLA expression ex vivo. However, regardless of viral specificity the levels of CLA are altered dramatically by cytokines, suggesting that the efficiency of skin homing of viral-specific CD8+ T cells can be influenced by the cytokine profile of the trafficking compartments through which the cells migrate. IL-4 caused significant down-regulation of CLA expression by viral-specific CD8+ T cells. Such a mechanism may potentially contribute to the relative susceptibility of individuals with atopic dermatitis to cutaneous viral infection.

Acknowledgments

We are most grateful to the Medical Research Council, British Skin Foundation and Barrie Trust for their support.

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