Skip to main content
NCBI home page
Immunology logoLink to Immunology
. 2007 Jan;120(1):66–72. doi: 10.1111/j.1365-2567.2006.02478.x

Interleukin-4 promotes human CD8+ T cell expression of CCR7

Suranjith L Seneviratne 1, Antony P Black 1, Louise Jones 1, Kati di Gleria 1, Abigail S Bailey 1, Graham S Ogg 1,2
PMCID: PMC2265870  PMID: 17073944

Abstract

Despite strong evidence supporting a pathway of human T cell differentiation characterized by changes in the expression of CCR7, CD28, CD27 and CD62L, few studies have addressed the mechanisms of pathway regulation. Cutaneous lymphocyte-associated antigen (CLA)-positive skin-homing CD8+ T cells expressed significantly elevated levels of activation markers compared with CLA− CD8+ T cells in individuals (n = 27) with cutaneous atopic disease. Despite such an activated phenotype, CLA+ T cells expressed significantly higher levels of CCR7 than a CLA− T cell subset. Interleukin (IL)-4 was found to dramatically promote CCR7 expression by antigen-specific CD8+ cells. Furthermore, skin-homing CD8+ T cells from individuals with severe disease produced significantly less IL-10 than those derived from mildly affected atopic subjects. Thus in a T-helper 2 dominated disease, tissue-specific CD8+ T cells show altered CCR7 expression and cytokine production, which may contribute to continued lymph node homing, antigen presentation and disease. IL-4 promotes expression of CCR7, a marker linked to existing models of CD8+ T cell differentiation.

Keywords: cytokines, cell differentiation, T cells, cutaneous lymphocyte associated antigen

Introduction

Differentiation of human T cells reflects changes in the expression of proteins that control cell cycle, survival, migration and effector functions. Numerous models have been proposed with considerable controversy regarding the phenotypic associations.1 Although it is broadly agreed that naive T cells express CD45RA, CCR7, CD62L, CD28 and CD27, the patterns with which these are lost (or subsequently re-acquired) following antigen encounter are under debate. For example, expression of the lymph node homing receptor CCR7 has been suggested to define progression from central memory (CCR7+) to effector memory (CCR7−) populations, and although these terms are widely employed, it is becoming increasingly clear that CCR7 can be re-acquired.2,3 The analysis of markers associated with T cell activation has also contributed to the controversy. It is relatively well accepted that several cell surface molecules are expressed transiently after interaction with cognate antigen including CD25, HLA-DR, CD38 and CD71.

More recently, a combination of CD28, CD27, CCR7 and CD45RA has been used to define a linear model of progression of antigen-experienced CD8+ T cells from early (CD27+, CD28+, CCR7−, CD45RA−) to intermediate (CD27+, CD28−, CCR7−, CD45RA+/−) to late (CD27−, CD28−, CCR7−, CD45RA+/−) differentiation, but it is recognized that the markers can be variable.1 Little is known of the mechanisms of regulation of expression of markers of human T cell differentiation, but transforming growth factor (TGF)-β is thought to promote the expression of CCR74 and interleukin (IL)-12 promotes murine CD62L.5

We have previously shown that cytomegalovirus (CMV)-specific CD8+ T cells express markers associated with activation and effector function, and putatively follow the linear differentiation pathway described above, being largely within the CCR7−, CD27−, CD28− late differentiated subset.6 However, human immunodeficiency virus (HIV)-specific CD8+ T cells frequently show partial defects in effector function and dominate within the CCR7+/−, CD27+, CD28+/− intermediate subset.3,6 To our knowledge, there are no data examining the influence of T helper (Th2) cytokines on markers linked to the progression of human CD8+ T cell differentiation. Understanding the events linked to T cell differentiation is important in order to define the role of T cells in disease pathogenesis and also to direct T cell-mediated therapies (e.g. vaccination) to the optimal induction or modification of particular relevant T cell subsets.

Having derived peripheral blood mononuclear cells (PBMCs) from individuals (n = 27) with cutaneous atopic disease, we observed that cutaneous lymphocyte-associated antigen (CLA)-positive skin-homing CD8+ T cells expressed significantly elevated levels of activation markers compared with CLA− CD8+ T cells. For classical viral-specific CD8+ T cells, this phenotype was associated with loss of CCR7 expression. However, by contrast, the activated CLA+ T cells expressed significantly higher levels of CCR7 than the CLA− T cell subset. We tested the hypothesis that Th2 cytokines might influence the expression of markers associated with differentiation. Human leucocyte antigen (HLA)-peptide tetrameric complexes were used to facilitate phenotypic analysis of human antigen-specific T cells following stimulation with cognate antigen in the presence or absence of IL-4, IL-5 and IL-13. IL-4 was found to dramatically promote CCR7 expression and to polarize CD8+ T cells towards a Tc2 phenotype. Furthermore, skin-homing CD8+ T cells were enriched for an allergen-specific subset, and cells from individuals with severe disease produced significantly less IL-10 than those derived from mildly affected atopic subjects. Thus in conclusion, IL-4 promotes the expression of CCR7, a marker currently linked to CD8+ T cell differentiation.

Materials and methods

Subjects

Fifteen severely symptomatic, 12 mildly symptomatic atopic individuals and 10 non-atopic controls were recruited through the Department of Dermatology, Churchill Hospital, Oxford under the ethical approval of the Oxfordshire Clinical Research Committee. Atopic dermatitis was defined according to the UK refinements of the Hanifin and Rajka diagnostic criteria for atopic dermatitis (AD), which are specific and sensitive for AD.7,8 The criteria require the presence of an itchy skin condition plus three or more of the following: onset below 2 years of age; history of skin crease involvement; history of generally dry skin; visible flexural dermatitis, and personal history of another atopic disease (or history of atopic disease in a first-degree relative). All severely symptomatic atopic patients had, by definition, a disease severity SASSAD (six-area, six-sign atopic dermatitis) score > 54 (of a possible total of 108).9 All individuals in the mildly affected group had a SASSAD score < 10. The SASSAD score is graded on a scale of 0–3 (absent to severe) for each of the six clinical features (erythema, exudate, excoriation, lichenification, dryness, cracking) at six sites (head/neck, thorax/proximal limbs, mid upper limbs, mid lower limbs, hands, feet). All the atopic subjects had positive skinprick tests and IgE radioallergosorbent tests (RAST) to housedust mite. None of the non-atopic subjects had a personal or family history of atopic disease and all had negative housedust mite skinprick tests and IgE RASTs. There were no statistically significant differences between the groups in the distribution of age, sex and racial origin. None of the patients had received systemic immunosuppressive treatment for the preceding 6 months.

HLA-peptide tetrameric complexes

Complexes were synthesized as previously described.10,11 Purified HLA heavy chain and β2 microglobulin were synthesized by means of a prokaryotic expression system (pET Novagen; EMD Biosciences, San Diego, CA). 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 were refolded by dilution with Epstein Barr virus (EBV) BMLF1 peptide 280–8 GLCTLVAML. The 45 kDa refolded product was isolated by fast protein liquid chromatography (FPLC), and then biotinylated by BirA (Avidity, Denver, CO) in the presence of biotin (Sigma, Gillingham, 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 fluorescence-activated cell sorter (FACS) Calibur (Becton Dickinson, Oxford, UK) with cellquest software (Becton Dickinson). 106 PBMC were centrifuged at 300 g for 5 min and resuspended in a volume of 50 µl R10 (RPMI-1640 medium (Gibco BRL, Paisley, UK) supplemented with 10% fetal calf serum (FCS) (Globepharm Ltd, Guildford, UK), 2 mm l-glutamine, 50 U/ml penicillin and 50 µg/ml streptomycin). Tetrameric complex was added and incubated at 37° for 20 min. Directly conjugated antibodies (including anti-CD8, anti-CLA, anti-CD62L, anti-CCR7, anti-CD28, anti-CD27, anti-CD45RA, anti-CD25, anti-HLA-DR) were added and the samples incubated for 60 min at 4°. After two washes in cold phosphate-buffered saline, the samples were fixed in 2% formaldehyde. Cytokine-specific antibodies were used as follows: phycoerythrin (PE) conjugated mouse anti-human IL-4, PE rat anti-human IL-13, PE rat anti-human IL-5, PE and fluorescein isothiocyanate (FITC) mouse anti-human interferon (IFN)-γ, PE mouse anti-human tumour necrosis factor (TNF)-α, PE-CD25, PE and FITC mouse IgG1, mouse IgG2b, rat IgG1, rat IgM, PerCP (peridinin chlorophyll protein) conjugated CD3 and allophycocyanin (APC) conjugated CD8 (all from Becton Dickinson), FITC rat anti-human IL-4 and PE rat anti-human IL-10 (all from Caltag, San Francisco, CA). For the phorbol myristate acetate (PMA)/ionomycin experiments, cells were stimulated for 4 hr in R10 medium containing 25 ng/ml PMA, 1 µg/ml ionomycin and 10 mg/ml Brefeldin A.

Statistics

Statistical analyses were performed using the chi-square, Fisher's exact and related t-tests and Pearson's correlation coefficient.

Antigen-specific T cell culture

PBMC were centrifuged for 5 min at 300 g and the supernatant removed. 100 µl of 200-µm filtered peptide was added and the cells incubated for 1 hr at 37° in 5% CO2. The cells were resuspended in R10 medium with IL-7 (25 ng/ml) in 24 well plates at 2 × 106 cells/ml. On day 4, IL-2 was added to a final concentration of 50 IU/ml. Other cytokines were used at the concentrations specified in the text. Peptides used for T cell culture and for synthesizing major histocompatibility complex (MHC)–peptide tetrameric complexes were synthesized at the laboratory in-house facility on an automated peptide synthesizer (396 MPS; Advanced Chemtech, Louisville, KY) by conventional solid phase Fmoc chemistry. These peptides were all analysed for purity by reverse phase high-performance liquid chromatography (HPLC). Cells were grown at 37° in 5% CO2, in R10 medium, unless otherwise stated. Cell lines were regularly screened for mycoplasma infection.

Results

Phenotypic analysis of skin-homing T cells

The expression of CD25, HLA-DR, CD38 and CD71 by CLA+ CD3+ T cells was significantly (P < 0·05) greater in individuals with severe atopic disease than those with mild disease. Specifically, the expression by CLA+ CD3+ T cells in those with severe disease compared with those with mild disease was: 43·1% vs. 25% CD25; 29% vs. 19·7% HLA-DR; 24·8% vs. 18·4% CD38, and 39·1% vs. 29·2% CD71. There was some variation in the intensity of CLA expression within the CLA+ population, and greater intensity of anti-CLA staining associated with higher levels of HLA-DR, CD38 and CD71 expression. CD69 expression on CLA+ CD3+ T cells was also investigated but the cells were virtually all negative, consistent with the finding that CD69 is an early marker of activation that is only briefly expressed. Furthermore, the CLA+ CD8+ T cells derived from atopic subjects (mild and severely affected) expressed significantly (P < 0·05) greater levels of activation markers than the CLA− CD8+ T cells. Specifically, the levels expressed by CLA+ CD8+ T cells compared with CLA− CD8+ T cells were: 32·2% (4·3) vs. 11·9% (5·3) CD25; 21·1% (6·2) vs. 9·2% (3·2) HLA-DR; 25·2% (1·9) vs. 8% (2·0) CD38, and 30% (4·3) vs. 15·9% (3·7) CD71 (standard deviations shown in brackets). Furthermore, the levels of activation markers expressed by CLA+ CD8+ T cells from atopic individuals (mild and severely affected) were significantly (P < 0·05) higher than those from non-atopic subjects (Table 1). Overall, these data suggest that CLA+ CD8+ T cells isolated from individuals with AD express markers of activation more frequently than CLA− CD8+ T cells, and are consistent with T cell recognition of persistent cutaneous atopic antigens.

Table 1.

Percentage (standard deviation in brackets) of specified T cells expressing markers of activation

CD25 HLA-DR CD38 CD71
CLA+ CD8+ atopics 32·2% (4·3)1 21·1% (6·2)1 25·2% (1·9)1 30·0% (4·3)1
CLA+ CD8+ non-atopics 12·2% (4·0) 6·0% (2·1) 7·5% (3·5) 14·3% (6·0)
Open in a new tab
1

Significant (P < 0·05) difference in expression of marker between CLA+ CD8+ T cells from atopic and non-atopic subjects.

Although both CD28 and CD27 expression by CLA+ CD3+ T cells in individuals with severe atopic disease were significantly (P < 0·05) lower than in those with mild disease, the differences were small, with the majority expressing both CD28 and CD27. Specifically, the levels in those with severe disease compared with those with mild disease were: 87% vs. 97% CD28, and 75% vs. 87% CD27. The levels of expression of CD28 and CD27 by CLA+ CD8+ T cells were not significantly different from levels expressed by CLA− CD8+ T cells (Table 2). However, the levels of CD62L and CCR7 were significantly higher (P < 0·01) in CLA+ CD8+ T cells than in CLA− CD8+ T cells (Table 2). By contrast, the EBV−tetramer binding cells expressed significantly lower levels of CD62L and CCR7 (Table 2). These levels of CCR7 and CD62L expressed by EBV-specific T cells were significantly (P < 0·01) lower than the levels for CLA+ CD8+ T cells. Therefore, in individuals with AD, tissue-specific CD8+ T cells do not show the expected loss of lymph node homing markers with increasing expression of markers of activation. We proceeded to test the hypothesis that Th2 cytokines could influence the expression of markers associated with differentiation.

Table 2.

Percentage (standard deviation in brackets) of specified T cells expressing markers of differentiation/homing

CD62L CCR7 CD28 CD27
EBV-specific CD8+ 7·6% (1·8) 15·8% (2·8) 67·4% (19·9) 93·0% (5·4)
CLA+ CD8+ 65·0% (7·6)12 72·8% (8·7)12 80·0% (5·4) 82·6% (6·2)
CLA− CD8+ 25·0% (6·2) 35·0% (4·2) 83·0% (5·0) 90·8% (4·1)
Open in a new tab
1

Significant (P < 0·01) difference in expression of marker between CLA+ CD8+ T cells and CLA−CD8+ T cells.

2

Significant (P < 0·01) difference in expression of marker between CLA+ CD8+ T and Epstein Barr virus (EBV)-specific CD8+ T cells.

Influence of Th2 cytokines on expression of differentiation markers by antigen-specific T cells

It is known that IL-4 induces downregulation of CLA by antigen-specific T cells12 and therefore we were unable to examine the influence of IL-4 on the expression of differentiation markers by CLA+ CD8+ T cells. Therefore, fluorescent HLA-peptide tetrameric complexes (tetramers) were generated based on HLA-A*0201 and refolded with the EBV BMLF1 A*0201-binding peptide 280–8 GLCTLVAML. Following incubation with cognate antigen, the cells were cultured with or without IL-4, IL-5, IL-9 and IL-13 (10 ng/ml) and analysed longitudinally. High affinity IL-4 receptors are expressed on resting T cells, and increase following activation. In addition, they are present on numerous other cell types, including haematopoietic stem cells, mast cells, macrophages, endothelial cells, fibroblasts, muscle cells and neuroblasts. We had not anticipated that IL-5 would induce direct changes, as CD8+ T cells are not known to express IL-5R, but IL-13Rα1 is widely expressed, including by heart, liver and skeletal muscle B and T cells. The levels of CD62L and CCR7 did not change significantly at days 5, 7, 10 and 14 when incubated in the absence of IL-4, IL-5 or IL-13. However, there were large significant (P < 0·01) increases in the expression of CCR7 in the presence of IL-4 (Fig. 1), which were maximal by day 5 and subsequently sustained. We were unable to examine earlier time-points due to the known T-cell receptor downregulation following ligation. Only minor changes were observed in the tetramer-negative population, suggesting that the influence of IL-4 is greatest following activation with cognate antigen. These findings were also confirmed using tetramer binding cells specific for a different virus, namely influenza (matrix peptide 58–66 GILGFVFTL). There was no influence on the expression of CD62L, CD28, CD27 or CD45RA by the cytokines. Figure 2 shows the dose–response of IL-4, IL-5 and IL-13 on the expression of CCR7 by antigen-specific CD8+ T cells. Levels of ≥ 10 ng/ml of IL-4 induced a significantly (P < 0·01) increased proportion of CCR7-expressing antigen-specific CD8+ T cells. EBV-specific CD8+ T cells were derived from both atopic and non-atopic subjects, and all showed significant increases in the proportion of CCR7-expressing CD8+ T cells in the presence of IL-4. Furthermore, consistent with previous reports, such levels of IL-4 were observed to polarize the EBV-specific CD8+ T cells towards a Tc2 phenotype with significantly increased production of IL-4 and less IFN-γ (data not shown). Overall, these data show that, in addition to known effects of IL-4 polarization towards a Tc2 phenotype, IL-4 promotes expression of CCR7 by viral-specific CD8+ T cells.

Figure 1.

Figure 1

Open in a new tab

Examples of expression of CD62L and CCR7 by CD8+ T cells after antigen-specific T cell culture in the presence of 100 ng/ml interleukin (IL)-4, IL-5 or IL-13. The top panel shows the sources of tetramer-negative and tetramer-positive CD8+ T cells for the remaining panels. The figures in the lower right corner of each histogram represent the proportion of cells in the CD62L− CCR7+ quadrant.

Figure 2.

Figure 2

Open in a new tab

Dose–response of the influence of interleukin (IL)-4, IL-5 and IL-13 on the expression of CCR7 by CD62L− tetramer-positive and tetramer-negative CD8+ T cells following incubation of peripheral blood mononuclear cells with specific peptide.

CLA+ CD8+ T cell cytokine production in individuals with cutaneous atopic disease

Progression along the intermediate and late differentiation programme is believed to be associated with acquisition of rapid effector function.1 Having established that in individuals with AD there was no significant loss of CCR7 despite increasing disease severity, cytokine production by CLA+ CD8+ T cells was investigated to determine whether there were functional associations. The CLA+ CD8+ T cells from both groups were able to produce both Tc1 and Tc2 cytokines but there were significant differences between those with severe atopic disease and those with mild atopic disease. The CLA+ CD8+ T cells derived from both groups were able to produce IFN-γ, TNF-α, IL-4, IL-5 and IL-13 but cells derived from severely affected atopics produced more IL-4, IL-5 and IL-13 than those derived from mildly affected individuals (Fig. 3). However, CLA+ CD8+ T cells from severely affected atopics produced significantly (P < 0·05) less IFN-γ and IL-10 than those derived from mildly affected atopic subjects.

Figure 3.

Figure 3

Open in a new tab

Percentage of ex vivo CD8− T cells that produce cytokines in response to phorbol myristate acetate/ionomycin. Open columns represent healthy controls (n = 10); hashed columns represent individuals with mild atopic disease (n = 12); solid columns represent individuals with severe atopic disease (n = 15). CLA+ CD8+ T cells from severely affected atopics produced significantly (*P < 0·05) less interferon (IFN)-γ and interleukin (IL)-10 than those derived from mildly affected atopics. Non-atopics produced significantly (P < 0·05) less IL-4, IL-5, IL-13 and more IFN-γ and tumour necrosis factor (TNF)-α than both mildly and severely affected atopic subjects.

Discussion

The current study provides the first data to document the influence of Th2 cytokines on markers linked to CD8+ T cell differentiation and shows that IL-4 strongly promotes expression of CCR7. Furthermore, it shows that skin-homing T cells maintain CCR7 expression despite escalating severity of atopic dermatitis and activation of the skin-homing T cells. The cell surface phenotype is associated with low IL-10 production, a cytokine pattern that has previously been suggested to contribute to atopic disease pathogenesis.13–22

The Hanifin and Rajka diagnostic criteria for AD have been refined and validated in many populations and, together with AD disease scoring systems, now allow for the rapid and reproducible identification and characterization of affected individuals.7–9 T cells are the dominant infiltrating population associated with lesional AD skin and include a significant proportion of CD8+ T cells.23,24 Cutaneous lymphocyte-associated antigen (CLA) is a carbohydrate-modified P-selectin glycoprotein ligand-1 and is believed to be a marker of cells that can interact with E-selectin.25–27 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 the rolling of CLA+ T cells along endothelium. CLA is expressed by the majority of T cells within cutaneous inflammatory infiltrates, but only by 5–20% of peripheral blood T cells. Increased frequencies of both CD4+ and CD8+ T cells producing type-2 cytokines (including IL-4, IL-5, IL-13) circulate in the peripheral blood of individuals with AD. This is particularly so within the putative skin-homing (CLA)-positive T cell subset.

In individuals with atopic disease, CLA+ CD8+ T cells express high levels of activation markers such as CD25, HLA-DR, CD38 and CD71, which is compatible with the transition from naive to antigen-experienced status and their role in the recognition of skin-associated antigens and contribution to cutaneous inflammation. However, despite increased expression of activation markers in those with severe disease, there was no concomitant loss of CCR7. In the absence of IL-4, antigen stimulation did not induce an upregulation of CD62L and CCR7 by CLA+ or CLA− T cells. Only minor changes were observed in the tetramer-negative population, suggesting that the influence of IL-4 is greatest following activation with cognate antigen. Although the expression of both CD62L and CCR7 were elevated on CLA+ CD8+ T cells compared with EBV-specific CD8+ T cells, only CCR7 expression was promoted by the addition of IL-4, suggesting that other factors might be important in the regulation of CD62L.5 In addition, IL-4 is known to induce CLA downregulation by antigen-specific T cells12 and thus overall may promote homing away from the skin and towards lymphoid tissue, potentially contributing to persistent T cell activation and expansion.

We have previously shown that HIV-specific T cells show an altered maturation pattern that associates with functional sequelae.3,6 Interestingly, chronic HIV infection has also been linked to a progressive Th2 shift, and thus the current data raise the possibility that it is the cytokine profile in infected individuals that influences T cell maturation and function.

The functional activity of CLA+ CD8+ T cells was investigated directly ex vivo and the cells were found to be a source of both type 1 and 2 cytokines, including IFN-γ, TNF-α, IL-4, IL-5, IL-13 and IL-10. However, in individuals with severe atopic disease, the CLA+ CD8+ T cells produced significantly less IL-10 than those derived from mildly affected atopics. These data may provide a mechanism for a number of other existing observations and are consistent with previous data. For example, IL-10 levels in bronchoalveolar lavage fluid from severely affected atopic subjects were found to be significantly lower than levels in mildly affected individuals.13 PBMCs from asthmatic subjects produced less IL-10 mRNA in response to lipopolysaccharide stimulation than those isolated from non-atopic subjects13 and low IL-10 producing promoter polymorphisms have been associated with severe asthma.14 Alveolar macrophages from asthmatics produced less IL-10 than those from non-atopic controls15 and, in Gabon, there was an inverse association between levels of IL-10 produced by PBMCs incubated with schistosomal antigens and skin test reactivity to housedust mite.16 Der p 1-specific CD8+ T cells from severely affected atopic individuals produce both Tc1 and Tc2 cytokines, but less IL-10 than those from mildly affected atopics,21 whereas CLA+ CD8+ T cells from non-atopic individuals are known to have the capacity to produce both Tc1 and Tc2 cytokines.28 One consequence of diminished IL-10 production may be a relative reduction in the regulatory ability to control immune responses to ubiquitous environmental allergens.

In summary, IL-4 was found to promote CCR7 expression by antigen-specific T cells, suggesting that the cytokine microenvironment may influence the differentiation of T cells with associated consequences for effector function and immune responses to persistent antigens. Thus IL-4 strongly influences CCR7, a marker that is linked to existing models of human CD8+ T cell differentiation, which requires us to re-evaluate our understanding of mechanisms of pathway regulation.

Acknowledgments

We are very grateful to the Medical Research Council, British Skin Foundation and Barrie Trust for their support. We are also most grateful to all the patients involved in the studies.

Glossary

Abbreviations:

AD

atopic dermatitis

CLA

cutaneous lymphocyte-associated antigen

CMV

cytomegalovirus

HIV

human immunodeficiency virus

PBMCs

peripheral blood mononuclear cells

References

  • 1.Appay V, Rowland-Jones SL. Lessons from the study of T-cell differentiation in persistent human virus infection. Semin Immunol. 2004;16:205–12. doi: 10.1016/j.smim.2004.02.007. [DOI] [PubMed] [Google Scholar]
  • 2.Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature. 1999;401:708–12. doi: 10.1038/44385. [DOI] [PubMed] [Google Scholar]
  • 3.Champagne P, Ogg G, King AS, et al. Skewed maturation of memory HIV-specific CD8+ T lymphocytes. Nature. 2001;410:106–11. doi: 10.1038/35065118. [DOI] [PubMed] [Google Scholar]
  • 4.Sallusto F, Lenig D, Mackay CR, Lanzavecchia A. Flexible programmes of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes. J Exp Med. 1998;187:875–83. doi: 10.1084/jem.187.6.875. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.van Wely CA, Beverley PC, Brett SJ, Britten CJ, Tite JP. Expression of 1-selectin on Th1 cells is regulated by IL-12. J Immunol. 1999;163:1214–21. [PubMed] [Google Scholar]
  • 6.Appay V, Dunbar PR, Callan M, et al. Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. Nat Med. 2002;8:379–85. doi: 10.1038/nm0402-379. [DOI] [PubMed] [Google Scholar]
  • 7.Williams HC, Burney PG, Hay RJ, et al. The UK Working Party's diagnostic criteria for atopic dermatitis. I. Derivation of a minimum set of discriminators for atopic dermatitis. Br J Dermatol. 1994;131:383–96. doi: 10.1111/j.1365-2133.1994.tb08530.x. [DOI] [PubMed] [Google Scholar]
  • 8.Williams HC, Burney PG, Pembroke AC, Hay RJ. Validation of the UK diagnostic criteria for atopic dermatitis in a population setting. UK Diagnostic Criteria for Atopic Dermatitis Working Party. Br J Dermatol. 1996;135:12–7. [PubMed] [Google Scholar]
  • 9.Berth-Jones J. Six-area, six-sign atopic dermatitis (SASSAD) severity score: a simple system for monitoring disease activity in atopic dermatitis. Br J Dermatol. 1996;135(Suppl 48):25–30. doi: 10.1111/j.1365-2133.1996.tb00706.x. [DOI] [PubMed] [Google Scholar]
  • 10.Altman JD, Moss P, Goulder P, Barouch DH, McHeyzer WM, Bell JI, McMichael AJ, Davis MM. Phenotypic analysis of antigen-specific T lymphocytes. Science. 1996;274:94–6. [Google Scholar]
  • 11.Ogg G, Jin X, Bonhoeffer S, Dunbar P, et al. Quantitation of HIV-specific CTL and plasma load of viral RNA. Science. 1998;279:2103–6. doi: 10.1126/science.279.5359.2103. [DOI] [PubMed] [Google Scholar]
  • 12.Seneviratne SL, Jones L, Bailey AS, Samuel RV, Black AP, Ogg GS. Interleukin-4 induced downregulation of skin homing receptor expression by human viral-specific CD8 T cells may contribute to atopic risk of cutaneous infection. Clin Exp Immunol. 2005;141:107–15. doi: 10.1111/j.1365-2249.2005.02823.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Borish L, Aarons A, Rumbyrt J, Cvietusa P, Negri J, Wenzel S. Interleukin-10 regulation in normal subjects and patients with asthma. J Allergy Clin Immunol. 1996;97:1288–96. doi: 10.1016/s0091-6749(96)70197-5. [DOI] [PubMed] [Google Scholar]
  • 14.Hobbs K, Negri J, Klinnert M, Rosenwasser LJ, Borish L. Interleukin-10 and transforming growth factor-β promoter polymorphisms in allergies and asthma. Am J Respir Crit Care Med. 1998;158:1958–62. doi: 10.1164/ajrccm.158.6.9804011. [DOI] [PubMed] [Google Scholar]
  • 15.John M, Lim S, Seybold J, Jose P, Robichaud A, O'Connor B, Barnes PJ, Chung KF. Inhaled corticosteroids increase interleukin-10 but reduce macrophage inflammatory protein-1α, granulocyte-macrophage colony-stimulating factor, and interferon-γ release from alveolar macrophages in asthma. Am J Respir Crit Care Med. 1998;157:256–62. doi: 10.1164/ajrccm.157.1.9703079. [DOI] [PubMed] [Google Scholar]
  • 16.van den Biggelaar AH, van Ree R, Rodrigues LC, Lell B, Deelder AM, Kremsner PG, Yazdanbakhsh M. Decreased atopy in children infected with Schistosoma haematobium: a role for parasite-induced interleukin-10. Lancet. 2000;356:1723–7. doi: 10.1016/S0140-6736(00)03206-2. [DOI] [PubMed] [Google Scholar]
  • 17.Zuany-Amorim C, Haile S, Leduc D, Dumarey C, Huerre M, Vargaftig BB, Pretolani M. Interleukin-10 inhibits antigen-induced cellular recruitment into the airways of sensitized mice. J Clin Invest. 1995;95:2644–51. doi: 10.1172/JCI117966. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Arock M, Zuany-Amorim C, Singer M, Benhamou M, Pretolani M. Interleukin-10 inhibits cytokine generation from mast cells. Eur J Immunol. 1996;26:166–70. doi: 10.1002/eji.1830260126. [DOI] [PubMed] [Google Scholar]
  • 19.Grunig G, Corry DB, Leach MW, Seymour BW, Kurup VP, Rennick DM. Interleukin-10 is a natural suppressor of cytokine production and inflammation in a murine model of allergic bronchopulmonary aspergillosis. J Exp Med. 1997;185:1089–99. doi: 10.1084/jem.185.6.1089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Wang B, Zhuang L, Fujisawa H, et al. Enhanced epidermal Langerhans cell migration in IL-10 knockout mice. J Immunol. 1999;162:277–83. [PubMed] [Google Scholar]
  • 21.Seneviratne SL, Jones L, King AS, Black A, Powell S, McMichael AJ, Ogg GS. Allergen-specific CD8 (+) T cells and atopic disease. J Clin Invest. 2002;110:1283–91. doi: 10.1172/JCI15753. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Reefer AJ, Carneiro RM, Custis NJ, Platts-Mills TA, Sung SS, Hammer J, Woodfolk JA. A role for IL-10-mediated HLA-DR7-restricted T cell-dependent events in development of the modified Th2 response to cat allergen. J Immunol. 2004;172:2763–72. doi: 10.4049/jimmunol.172.5.2763. [DOI] [PubMed] [Google Scholar]
  • 23.Sager N, Feldmann A, Schilling G, Kreitsch P, Neumann C. Housedust mite-specific T cells in the skin of subjects with atopic dermatitis: frequency and lymphokine profile in the allergen patch test. J Allergy Clin Immunol. 1992;89:801–10. doi: 10.1016/0091-6749(92)90434-4. [DOI] [PubMed] [Google Scholar]
  • 24.Akdis M, Simon HU, Weigl L, Kreyden O, Blaser K, Akdis CA. Skin homing (cutaneous lymphocyte-associated antigen-positive) CD8+ T cells respond to superantigen and contribute to eosinophilia and IgE production in atopic dermatitis. J Immunol. 1999;163:466–75. [PubMed] [Google Scholar]
  • 25.Fuhlbrigge RC, Kieffer JD, Armerding D, Kupper TS. Cutaneous lymphocyte antigen is a specialized form of PSGL-1 expressed on skin-homing T cells. Nature. 1997;389:978–81. doi: 10.1038/40166. [DOI] [PubMed] [Google Scholar]
  • 26.Fuhlbrigge RC, King SL, Dimitroff CJ, Kupper TS, Sackstein R. Direct real-time observation of E- and P-selectin-mediated rolling on cutaneous lymphocyte-associated antigen immobilized on Western blots. J Immunol. 2002;168:5645–51. doi: 10.4049/jimmunol.168.11.5645. [DOI] [PubMed] [Google Scholar]
  • 27.Teraki Y, Miyake A, Takebayashi R, Shiohara T. In vivo evidence for close association of CLA expression and E-selectin binding by T cells in the inflamed skin. J Dermatol Sci. 2004;36:63–5. doi: 10.1016/j.jdermsci.2004.07.009. [DOI] [PubMed] [Google Scholar]
  • 28.Teraki Y, Hotta T, Shiohara T. Skin-homing interleukin-4 and -13-producing cells contribute to bullous pemphigoid: remission of disease is associated with increased frequency of interleukin-10-producing cells. J Invest Dermatol. 2001;117:1097–102. doi: 10.1046/j.0022-202x.2001.01505.x. [DOI] [PubMed] [Google Scholar]

Articles from Immunology are provided here courtesy of British Society for Immunology

RESOURCES