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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Autoimmun. Author manuscript; available in PMC Aug 5, 2011.
Published in final edited form as:
PMCID: PMC3150737
NIHMSID: NIHMS311670

Phenotypical and functional alterations of CD8 regulatory T cells in primary biliary cirrhosis

Abstract

The mechanisms that lead to loss of tolerance in autoimmune disease have remained both elusive and diverse, including both genetic predisposition and generic dysregulation of critical mononuclear cell subsets. In primary biliary cirrhosis (PBC), patients exhibit a multilineage response to the E2 component of pyruvate dehydrogenase involving antibody as well as autoreactive CD4 and CD8 responses. Recent data from murine models of PBC have suggested that a critical mechanism of biliary destruction is mediated by liver-infiltrating CD8 cells. Further, the number of autoreactive liver-infiltrating CD4 and CD8 cells is significantly higher in liver than blood in patients with PBC. Based on this data, we have studied the frequencies and phenotypic characterization of both CD4 and CD8 regulatory T cell components in both patients with PBC and age–sex matched controls. Our data is striking and indicate that CD8 Treg populations from PBC patients, but not controls, have significant phenotypic alterations, including increased expression of CD127 and reduced CD39. Furthermore, in vitro induction of CD8 Tregs by incubation with IL10 is significantly reduced in PBC patients. Importantly, the frequencies of circulating CD4+CD25+ and CD8+ and CD28− T cell subpopulations are not significantly different between patients and controls. In conclusion, these data identify the CD8 Treg subset as a regulatory T cell subpopulation altered in patients with PBC.

Keywords: Autoimmune cholangitis CD8 T regulatory cells, IL7-R, CD39

1. Introduction

Primary biliary cirrhosis (PBC) is a chronic inflammatory disease of the liver characterized by progressive destruction of small and medium size intrahepatic bile ducts leading to cirrhosis and may ultimately require liver transplantation for survival [1]. Genetic, environmental and immunological factors have all been shown to contribute to the pathogenesis of PBC [2,3]. In particular, the presence of circulating autoantibodies, mainly directed to mitochondrial and nuclear antigens (AMA and ANA, respectively), is the hallmark of PBC [4]. Furthermore, affected livers from PBC patients are heavily infiltrated by both CD4 and CD8 T lymphocytes [5]. Such liver cell infiltrates are highly enriched for T cells reactive against mitochondrial autoantigens (E2 subunits of the pyruvate dehydrogenase complex) [6,7]. Finally, alterations in a number of other cell lineages have also been documented, including the frequency of NK and Th17 cells and function [8,9]. Despite this extensive and critical evaluation of both autoantibody and autoreactive T cells, the mechanisms that lead to loss of tolerance has proven elusive. From a generic perspective there is considerable discussion that suggests that deficiencies in the regulatory T cell compartments are responsible for antigen specific loss of tolerance [1012]. However, this has been difficult to prove in humans and further, despite widely observed, quantitative and/or functional impairments of regulatory T lymphocytes in humans and animal models, it has been difficult to link these observations to liver specific autoimmunity.

PBC is overwhelmingly a syndrome of adults, although interestingly, there is a PBC-like disease reported in a child with IL-2 receptor α (CD25) deficiency [13]. This observation is interesting because there is data from murine models of autoimmune cholangitis that support a deficiency of CD25 expression, impairing Treg function that leads to liver pathology [1416]. In this respect we note that CD8 T cells play a critical role in loss of CD4+ Treg function in mice [17]. We should also note that quantitative and functional analysis of intrahepatic and circulating Tregs in humans with PBC suggest a loss of T regulatory function [1820], but these studies have focused entirely on CD4+CD25 Treg cells. Based on the murine data, suggesting a role for CD8 Treg populations, we have specifically addressed and analyzed both CD24+CD25+ and CD8+CD28− Tregs. Our data suggest a defect in CD8 Tregs in patients with PBC and we submit that these cells reflect a dysregulatory population that leads to the loss of tolerance in PBC.

2. Materials and methods

2.1. Patients

The studies reported herein included a total of 15 patients with PBC; all patients were female and ranged from 42 to 80 years of age. The first 11 AMA positive patients were consecutively enrolled without any bias. In addition, four well-documented AMA negative patients with PBC were also included. In all cases, the diagnosis was based on internationally accepted criteria which required the fulfilment of at least two of the following features: elevated serum alkaline phosphatase levels for longer than six months, compatible or diagnostic liver histology, and positive serum AMA [1]. All patients underwent informed consent. Of these 15 patients, 12/15 had Ludwig’s histologic stages III–IV and 3/15 had stage I/II [21]. At the time of enrolment, all patients were receiving ursodeoxycholic acid (UDCA) at a dose of 12–15 mg per kilogram of body weight per day for at least 6 months as the only form of treatment. To address the possible role of UDCA, 5 patients consented to a 2-month UDCA wash-out period and the same studies were repeated. These 5 patients served as a nested subset that allowed to test both the reproducibility of the data as well as the potential role of UDCA. The demographics and disease characteristics of all patients enrolled in the study are summarized in Table 1. In addition, fifteen age and sex-matched healthy donors were studied as controls. Reproducibility was evaluated by analysing two different blood samples from 6 out of the 15 PBC patients and 5 of the 15 healthy controls.

Table 1
Clinical, biochemical and serological characteristics of PBC patients.

2.2. Immunofluorescence analyses

Peripheral blood mononuclear cells (PBMC) were isolated by centrifugation on a Ficoll-Hypaque gradient for 30 min at 1800 rpm. The cell surface markers expressed by lymphoid cell subsets were determined using standard flow cytometry. Aliquots of the gradient purified lymphocytes (1 × 105 cells in 100 μl of PBS) were incubated with specific mAbs at 4 °C for 30 min in the dark. To characterize the phenotype of CD4+ Tregs and CD8+CD28− Treg the following mAbs were used: APC conjugated anti-CD3, PE-conjugated anti-CD25, PerCP 5.5 conjugated anti-CD8, FITC-conjugated and anti-CD4, phycoerythrin or fluorescein isothiocyanate conjugated anti-CD28, phycoerythrin conjugated anti-CD25, allophycocyanin–cyanin 7 conjugated anti-CD3 FITC-conjugated anti-CD45RA, PE-conjugated anti-CD127, PE-conjugated anti-CCR7 (all from BD Biosciences, Franklin Lakes, NJ USA). Isotype-matched, FITC- or PE-conjugated mAbs, specific for non-relevant antigens, were used as negative controls. After staining procedures the cells were acquired and analyzed by a FACSCan to flow cytometer (BD Biosciences) using the FACSDIVA software. All analysis was performed in a “blinded” fashion with the evaluator unaware of whether the data was obtained from a patient or a control.

2.3. Purification of CD4+CD25+ and CD8+CD28− T lymphocytes

Highly enriched populations of CD4+CD25+ and CD8+CD28− T cell subsets were isolated from PBMC by sequential cycles using commercially available magnetic beads (Milenyi Biotec, Bergisch Gladbach, Germany). While the CD4+CD25+ regulatory T cell isolation kit was used for purification of CD4+CD25+ T cells, the MultiSort CD8 microBeads followed by depletion using microbeads conjugated with the anti-CD28 9.3 monoclonal antibody (mAb) [22] were used for the purification of CD8+CD28− T lymphocytes. The purity of sorted cells resulted ≥95% as demonstrated by flow cytometric analysis. The viability of cells was always >95%.

2.4. In vitro generation of CD8 Tregs from PBMC of PBC patients and controls

Purified CD8+CD28− T lymphocytes (1 × 105 cells/well) were re-suspended in culture medium, consisting of RPMI 1640 (Invitrogen, Carlsbad, CA, USA) including 10% fetal calf serum, 2% glutamine and penicillin 100 U/ml-streptomycin 0.1 mg/ml (Sigma, St. Louis, MO, USA). The cells were then incubated with or without 20 U/ml of IL-2 (Chiron, Emeryville, CA, USA) and 40 ng/ml of IL10 (R&D System, McKinley Place NE, MN, USA), in 96 well flat bottomed plates (Corning Costar, Lowell, MA, USA) at 37 °C for 7 days. At the end of the incubation period the cells were collected, washed and used as suppressors in a proliferation suppression assay.

2.5. Proliferation suppression assay

PBMC pulsed with the anti-CD3 UCTH-1 mAb (5 μg/ml) were cultured for 5 days in a 96 well flat bottomed plate (1 × 105 cells/well) in the presence (or absence) of either CD4+CD25+ Treg or ex vivo freshly isolated CD8+CD28− T lymphocytes or in vitro generated CD8 Treg (1 × 105 cells/well). Twelve hours before harvesting, 0.5 μCi of 3H-thymidine were added to each well. The radioactivity of cells from individual wells was measured by a beta-counter (Hidex Oy, Mustionkatu 2, Finland).

2.6. Statistical analysis

All results are expressed as mean ± standard deviation. The chi-square or Fisher’s exact test was used to derive statistical data. For the analysis of continuous variables, the Student’s t and Mann–Whitney U tests were used to compare two groups. P values less than 0.05 were defined as significant. All of the analyses were two-tailed. The statistical comparisons were made using GraphPad Prism 4.0 Software (GraphPad Software, Inc, La Jolla, CA, USA).

3. Results

3.1. Altered expression of CD127 and CD39 on CD8 Treg from PBC patients

Although no selective cell surface markers have yet to be identified that uniquely identifies Tregs, it is widely accepted that CD4+CD25 +hi and CD8+CD28− phenotypic patterns identify the majority of Tregs belonging to either the CD4 or the CD8 T cell lineages, respectively [23,24]. Hence, in order to achieve information on the frequency of both Treg subpopulations in the peripheral blood of PBC patients, their frequency and absolute numbers were comparatively analyzed in blood samples from PBC patients and healthy subjects. Similar frequencies of circulating CD4+CD25+ among CD4 cells were found in PBMC samples from PBC patients and compared with healthy controls (1.08% vs 1.31%, P = 0.32), and the same for CD8+CD28− among CD8 cells (38.46% vs 47%, P = 0.2). It was reasoned that in the absence of numerical defects, qualitative alterations could be at play in determining the functional dysregulation of the Treg compartment. Hence, the phenotypic patterns expressed by both the CD4 and CD8 Treg subsets were evaluated in PBC patients taking into consideration the expression of CD127 (the IL7-R), IL10Ra, CCR7, GITR, CD39, CD49d membrane molecules. The analyses performed on ex vivo isolated CD4+CD25+ Treg did not show any significant difference as compared with values obtained with cells from healthy subjects (data not shown). Concerning the CD8 T cell compartment, both in vitro generated CD8 Treg (Fig. 1a and c) and ex vivo freshly isolated CD8+CD28− T cells (Fig. 1b and d) were studied. Remarkably, the frequency of CD127+ cells was found significantly enhanced in in vitro generated CD8 Treg from PBC patients as compared with cells from healthy subjects (Fig. 1a), which is likely due to the down modulation during the generation of Treg function induced by incubation with IL10. Moreover, in vitro generated CD8 Tregs from PBC patients showed decreased expression of the CD39 antigen as compared with cells from control (Fig. 1c). These findings demonstrate that in PBC patients CD8 Treg are affected with phenotypic alterations potentially contributing to their function. No significant differences in the expression of CD127 and CD39 were noted in samples from PBC patients prior to (Fig. 1b and d) and following UDCA withdrawal (not shown). In addition, no significant differences were also noted in the frequency and density of cells that expressed IL10Ra, CCR7, GITR and CD49d (not shown) in samples from PBC patients as compared with controls. In 6 patients with PBC and 5 healthy subjects two blood samples were analyzed to test the reproducibility of the data and we obtained similar results (not shown).

Fig. 1
Analysis of the expression of the CD127 and CD39 antigen on CD8 Tregs from PBC patients and healthy subjects. Panel a: Percentage of CD127 positive cells in in vitro generated CD8 Treg from PBC patients and healthy controls and comparison of the mean ...

3.2. Altered suppressive activity of CD8 Treg from PBC patients

In order to verify whether the phenotypic anomalies observed on CD8 Treg from PBC patients could be related to altered function, the suppressive activity of CD8 Treg from PBC patients was analyzed in comparison with that of control cells. Again, the analysis was performed on both ex vivo freshly isolated CD8+CD28− T cells and in vitro generated CD8 Treg. The suppressive activity of CD4+CD25+ T cells was analyzed in parallel with the aim to eventually unveil functional deficits affecting both Treg subpopulation. Ex vivo freshly isolated CD8+CD28− T cells demonstrated significant suppressive activity (≥25% –threshold for significant suppressive activity) in 7 out of 15 PBC patients, which was not noted in similar cells from control subjects. However, incubation of circulating CD8+CD28− T cells with IL10 failed in the in vitro generation of CD8 Treg to exert suppressive activity in 10 out of 15 PBC patients. Notably, similar in vitro incubation with IL10 led to the generation of CD8 Tregs in 100% of the healthy controls. Indeed, the mean percent suppressor activities of CD8 Treg from PBC patients was significantly lower than in controls (13.93% vs 67.13%, P = 0.0001) (not shown). No significant differences were detected in samples from PBC patients prior to influencing UDCA and treated or not treated with UDCA (not shown). No alteration of the suppressive activity of CD4+CD25+ Treg was detected in our series of PBC patients compared to controls (70.62% vs 64.62%, P = 0.19) (not shown). In a nested subset of 6 patients with PBC and 5 healthy subjects we analyzed two blood samples in parallel and we obtained similar results (not shown).

4. Discussion

The results of this study demonstrate that: a) the frequencies and absolute numbers of circulating CD4+CD25+ and CD8+CD28− T cell subpopulations do not significantly differ in PBC patients as compared with healthy controls; b) CD8 Tregs from PBC patients reflect increased expression of CD127 and reduced expression of CD39; c) the in vitro generation of CD8 Treg by incubation of cells with IL10 was markedly compromised in cells from PBC patients leading to deficient suppressor activity.

One leading hypothesis on the pathogenesis of autoimmune diseases proposes the existence of an unbalanced ratio between effector and regulatory arms of the immune system [12,2532]. In particular, numerical and/or functional impairments of Treg are postulated to be at play. Indeed, alterations of circulating Treg have been demonstrated in several autoimmune diseases [10] including rheumatoid arthritis [33,34], systemic lupus erythematosus [3539], autoimmune thyroiditis [4042], type 1 diabetes mellitus [43,44] and multiple sclerosis [45]. In particular, the most common finding has been the decreased number of circulating CD4+CD25+ Treg.

In PBC, both autoreactive CD4 and CD8 T cells are clearly involved in the pathogenesis of PBC and liver infiltration of these cells is one of the major features of the disease [3]. However, a growing number of findings point to a predominant role for the CD8 T subpopulation in PBC [17,46]. Also, data support the role of Treg in various murine models of autoimmune cholangiopaties [1417]. In contrast, scanty and conflicting data are available on the frequency and function of circulating and liver-infiltrating CD4+CD25+ Treg in patients with PBC [1820]. In the current study, we confirm in an independent series that PBC patients have a normal frequency of CD4+CD25+ Treg in the peripheral blood [18], which indicates that the pathogenic mechanisms in PBC is different from that involved in others autoimmune diseases. Indeed, this assessment is supported by the finding of a normal suppressive function exerted by these cells in PBC patients.

CD8+CD28− T cells constitute the T cell subpopulation which includes the CD8 Treg precursors [47]. In particular, CD28, a major co-stimulatory receptor, is considered responsible for the optimal antigen-mediated T cell activation, proliferation and survival of T cells. Moreover, it has been demonstrated that the accumulation of CD8+CD28− T cells is a key change during T cell homeostasis and function associated with aging in humans [48,49].

In our series of patients with PBC circulating CD8+CD28− T cells, although numerically unaltered, were found unable to mount a regulatory immune response, upon incubation with IL10 in 10 out of 15 (66%) patients. Thus, qualitative defects affecting the CD8 Treg function are likely at play as exemplified by their reduced capacity to generate effective Treg cells. Unfortunately, in the absence of specific markers identifying CD8 Treg precursors, it is not possible at the moment to achieve quantitative data relative to the exact frequency of these cells in the circulation. Concerning qualitative defects, two phenotypic alterations were identified in this study: the increased expression of the CD127 antigen and the reduced/absent expression of the CD39 molecule. The CD127 antigen, the receptor for IL7, is mainly expressed on effector cells, being physiologically down modulated on Treg [50]. Thus, its elevated expression on CD8 Treg likely indicates the maintenance of effector activities by these cells and their resistance at being committed to Treg function [51]. The CD39 antigen is a nucleosidase present at the cell surface whose activity has been strictly correlated with normal Treg function [52,53]. Interestingly, it was found lowered on in vitro generated CD8 Tregs, indicating the impairment of the CD39-dependent mechanism of suppression in these cells.

Collectively, our study demonstrates that both reduced generation and altered function of CD8 Treg coexist in PBC patients, hence suggesting the presence of a profound alteration of the CD8 T cell-dependent regulatory circuit. In this scenario, the finding that ex vivo freshly isolated CD8+CD28− T cells from 6 out of 15 (40%) PBC patients spontaneously exert suppressor activity, an unexpected finding since this was not observed in healthy subjects, is relevant. In fact, it may suggest that the immune system of PBC patients tries to respond to the chronic inflammatory process and compensation for the impaired activity of CD8 Treg by targeting their generation at the immune competent tissue sites by inducing their homing to the liver from the circulation. Likely this process progressively decreases the reservoir of CD8 Treg precursors worsening the balance between pathogenic and regulatory immune responses. Altogether, such observations seems to suggest that PBC pathogenesis involves a defect of the CD8 Treg lineage, similarly to other autoimmune diseases [35,54]. Collectively, our data indicates that PBC is an autoimmune disease, which appears to involve a defect of a specific Treg subpopulation, the CD8 Treg, which is not only dysfunctional but its generation for progenitor cells may be impaired. Finally, we join the other contributors to the special volume in congratulating Dr. Harry Moutsopoulos for his contributions and his recognition in this special series on distinguished immunologists in the Journal of Autoimmunity and Autoimmunity Reviews [5558].

Acknowledgments

This work was supported in part by U.S. National Institutes of Health (R01 DK056839), M.I.U.R. grant #2006065999 and a grant from Compagnia di San Paolo, Torino, entitled “Tolerogenic gene immunization and adoptive suppressor cell transfer as therapies for systemic lupus erythematosus”

Abbreviations

PBC
primary biliary cirrhosis
AMA
anti-mitochondrial antibodies
ANA
anti-nuclear antibodies
Treg
regulatory T lymphocytes
UDCA
ursodeoxycholic acid
PBMC
peripheral blood mononuclear cells
IgG
immunoglobulin G
IgM
Immunoglobulin M

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