CD70–CD27 ligation between neural stem cells and CD4+ T cells induces Fas–FasL-mediated T-cell death
© Lee et al.; licensee BioMed Central Ltd. 2013
Received: 19 September 2012
Accepted: 9 May 2013
Published: 21 May 2013
Neural stem cells (NSCs) are among the most promising candidates for cell replacement therapy in neuronal injury and neurodegenerative diseases. One of the remaining obstacles for NSC therapy is to overcome the alloimmune response on NSCs by the host.
To investigate the mechanisms of immune modulatory function derived from the interaction of human NSCs with allogeneic T cells, we examined the immune regulatory effects of human NSCs on allogeneic T cells in vitro.
Significantly, NSCs induced apoptosis of allogeneic T cells, in particular CD4+ T cells. Interaction of CD70 on NSCs and CD27 on CD4+ T cells mediated apoptosis of T cells. Thus, blocking CD70–CD27 interaction prevented NSC-mediated death of CD4+ T cells.
We present a rational explanation of NSC-induced immune escape in two consecutive stages. First, CD70 constitutively expressed on NSCs engaged CD27 on CD4+ T cells, which induced Fas ligand expression on CD4+ T cells. Second, CD4+ T-cell apoptosis was followed by Fas–Fas ligand interaction in the CD4+ T cells.
KeywordsNeural stem cells Co-stimulatory molecules Immune escape mechanism
Neural stem cells (NSCs) are among the most promising candidates for cell replacement therapy in neuronal injury and neurodegenerative diseases. Derivation methods to produce neuronal cells with specific functions from NSCs, such as dopaminergic neurons, have also been established . Therefore, it is highly likely that NSCs will become the first choice for stem cell treatment.
Most cellular and organ transplantation between two unrelated individuals results in graft rejection. However, it has been often found that stem cell transplantation could escape the graft rejection [2–4], presumably by inducing apoptosis of T cells via Fas–Fas ligand (FasL) interaction .
Transplantation of rodent embryonic stem cells (ESCs) into allogeneic recipients indicated that they may have immune-privileged properties. The injection of undifferentiated rat ESC-like cells into fully MHC-mismatched rats led to the induction of donor-specific immunological tolerance . Moreover, undifferentiated allogeneic murine ESCs led to engraftment of these cells in the thymus, spleen and liver, with establishment of mixed hematopoietic chimerism . This also proved that ESCs represent a good research tool for possible therapeutic applications in solid organ transplantation because of their capability, when given alone, to induce tolerance to semi-allogeneic solid organ allograft .
NSC transplantation could be applied to the brain because this organ is subject to less surveillance by the immune system than other parts of the body, and like brain cells NSCs may display characteristics of cells with immune privilege. Consistent with this idea, T cells that infiltrate around transplanted NSCs in a stroke model exhibited little alloimmune response , suggesting NSCs have a strong potential to protect cells of the central nervous system against harmful T-cell infiltration . In a related study, the systemic injection of neuronal stem/precursor cells provided a remarkable amelioration of the pathological features of experimentally induced autoimmune encephalomyelitis and other preclinical models of neurological disorders [11, 12].
In this paper, we have investigated the mechanisms responsible for NSC-induced immune tolerance. Our studies indicate a two-stage model whereby human NSCs induce apoptosis of allogeneic CD4+ T cells. First, CD70 expressed constitutively on NSCs engage CD27 on CD4+ T cells and induce upregulation of FasL expression on the CD4+ T cells. Second, T cells thereafter undergo apoptosis from fratricide; that is, through Fas–FasL interaction in the CD4+ T cells themselves.
Materials and methods
The immortalized human embryonic neural stem cell line, HB1.F3 was generated in a previous study by transfection of primary cells from fetal human telencephalon tissue of 14 weeks gestation with amphotropic, replication-incompetent retroviral vector containing v-myc. Primary NSCs were provided by Professor Kim (Korea University, Seoul, Korea) [14, 15]. HB1.F3 cells and primary NSCs were cultured in DMEM with 10% heat-inactivated fetal bovine serum (Gibco, Carlsbad, CA, USA), and 1% antibiotic–antimycotic solution (Gibco, Carlsbad, CA, USA). Human umbilical cord blood mesenchymal stem cells purchased from MEDIPOST Co., Ltd (Seoul, Korea) were used. Human umbilical cord blood-derived mesenchymal stem cells were isolated and expanded as described previously [16, 17]. Cultures were maintained in a humidified incubator at 37°C containing 5% CO2.
CD4+ and CD8+ T-cell preparation
Whole blood was collected from healthy volunteer donors (n = 55, age: 24.85 ± 3.52, sex: male/female = 36/19). The institutional review board of the Seoul National University Hospital approved this study, and all volunteers provided written informed consent. Peripheral blood mononuclear cells were isolated by Ficoll-Paque PLUS (Amersham Biosciences, Piscataway, NJ) density gradient centrifugation of peripheral venous blood . The peripheral blood mononuclear cells were separated into CD4+ and CD8+ T-cell populations by magnetic-activated cell separation (Miltenyi Biotec, Bergisch Gladbach, Germany).
Co-culturing T cells with neural stem cells
To determine NSC-dependent apoptosis, CD4+ or CD8+ T cells were cultured with HB1.F3 at a density of 5 × 104:5 × 103, 5 × 104:1 × 104, 5 × 104:2.5 × 104, 5 × 104:5 × 104, and 5 × 104:1 × 105 cells/well on 96-well plates in well media. Adherent NSCs and nonadherent T cells were separately harvested at the indicated times and washed in 1× PBS.
Analysis of T-cell apoptosis
Apoptotic cell death was assessed using Annexin V staining coupled with propidium iodide (BD PharMingen, San Diego, CA, USA). T cells were cultured with HB1.F3 at a various densities or times. T cells were washed twice with 1× PBS. Then 2 × 105 to 5 × 105 T cells were added to a 12 mm test tube and washed twice in 1 ml of 1× binding buffer. Cells were mixed gently with 5 μl Annexin V–fluorescein isothiocyanate and incubated at 4°C in the dark for 5 minutes. After washing with binding buffer, 10 μl of the 20 μg/ml propidium iodide solution (end concentration 1 μg/ml) and 190 μl binding buffer were added to the cells. Cells were immediately analyzed by fluorescence-activated cell sorting (FACS).
Adherent NSCs were trypsinized and resuspended in staining buffer (0.1% BSA in PBS) to reach a final concentration of 5 × 105 to 1 × 106 cells/ml. The cells were incubated for 20 minutes on ice with the following antibodies: anti-CD27 (O323), anti-CD70 (Ki-24), anti-Fas (APO-1), anti-FasL (NOK-1), anti-PD-1 (J105), anti-PD-L1 (MIH1), anti-TR-1 (DJR1), anti-TR-2 (DJR2-4), and anti-TRAIL (RIK-2). After incubation, the cells were washed twice with staining buffer and resuspended. The stained cells were analyzed by FACS.
Total RNA was prepared from CD4+ T cells using the RNA isolation kit (QIAGEN Inc, Valencia, CA, USA). Two micrograms of RNA were reverse-transcribed. The reaction mixture consisted of 20 mM Tris–HCl (pH 8.4), 50 mM KCl, 5 mM MgCl2, 10 mM dithiothreitol, 40 U of RNaseOUT™, 1 mM dNTP, 2.5 μM of oligo(dT)20, 200 U of SuperScript™ III reverse transcriptase (Invitrogen, Carlsbad, CA, USA) and the remaining volume was diethylpyrocarbonate-treated water for a total volume of 20 μl. The mixture was incubated at 50°C for 1 hour, and at 85°C for 5 minutes. For semiquantitative PCR, the reaction mixture consisted of 10 mM Tris–HCl, 50 mM KCl, 0.1% Triton X-100, 2 mM MgCl2, 0.4 mM dNTP, 0.2 pmol sense and antisense primer, 2.5 U Taq DNA polymerase and 3 μg cDNA. Primer sequences are provided in Additional file 1.
HLA-A, HLA-B and HLA-DR allele on HB1.F3 cells
We examined HLA-A, HLA-B, and HLA-DR alleles on HB1.F3 cells using the PCR sequence-specific oligonucleotide method (Dynal RELI™ HLA typing kit, Dynal Biotech, Wirral, U.K.) . The results are provided in Additional file 2.
Treatment of anti-human Fas ligand mAbs
CD4+ T cells were incubated with HB1.F3 for 24 hours with a series of concentrations of neutralizing Fas ligand mAb (NOK-2): 0, 0.01, 0.1, 0.5, and 1 μg/ml.
Treatment of actinomycin D and cycloheximide
We treated a transcription inhibitor, actinomycin D (1 μg/ml; Sigma-Aldrich, St. Louis, MO, USA), on CD4+ T cells for 1 hour before co-culture with HB1.F3. The cells were co-cultured for 0 to 18 hours, and death ligand on CD4+ T cells was assessed at the transcriptional level by RT-PCR. We treated a translation inhibitor, CHX (10 μg/ml, Sigma-Aldrich, St. Louis, MO, USA) on T cells for 12 hours before co-culture with HB1.F3. The cells co-cultured for 12 hours, and intracellular Fas ligand expression on CD4+ or CD8+ T cells and HB1.F3 was assessed by FACS.
Treatment of anti-human CD27 or CD70 mAbs
CD4+ T cells were incubated with HB1.F3 for 12 hours with a series of concentrations of anti-CD27 (LG.7F9) or anti-CD70 mAb (BU69): 0, 0.01, 0.1, 0.5, and 1 μg/ml.
Combinatory treatment of anti-CD27, anti-PD-L1, or anti-CD40 mAb
CD4+ T cells were incubated with HB1.F3 for 24 hours with 0.5 μg/ml of anti-CD27 (LG.7F9), anti-PD-L1 (MIH-1), or anti-CD40 mAb (5C3).
All results are expressed as the mean ± standard deviation. The statistical significance of differences between group means was determined using Student’s t test.
Human neural stem cells induce CD4+ T-cell apoptosis
Fas–Fas ligand interaction is involved in neural stem cell-induced T-cell apoptosis
Neural stem cells induce Fas ligand upregulation on T cells
CD70–CD27 interaction is involved in neural stem cell-induced CD4+ T-cell death
Immune escape induced by stem cells is partly due to reduced expression of several cell surface molecules of immune activation on stem cell surfaces. For example, reduced alloreactivity caused by lack of MHC II and reduced MHC I expression on ESCs has been reported . Others have reported that stem cells induced T-cell apoptosis by Fas–FasL interaction, which had been observed to be one of the immune escape mechanisms on T cells [5, 30].
CD4+ T-cell apoptosis seemed to continuously occur even 24 hours after the co-culture, because the number of propidium iodide-positive cells continuously increased even after the number of Annexin V-positive cells reached its peak at 24 hours. However, it has not been clearly demonstrated whether this reaction was caused by direct interaction between the FasL expressed on the surface of NSCs and Fas on CD4+ T cells. Similar to other researchers' observations of human ESCs in various stages of differentiation , we could not detect either FasL mRNA or surface protein by FACS in NSCs. FasL expression on HB1.F3 was examined using FACS analysis and immunocytochemistry. Both results showed an absence of FasL on HB1.F3, which was similar to the previous results of a study performed with ESCs . Direct Fas–FasL interactions between NSC and CD4+ T cells are therefore less likely to occur (see Additional file 3). NSCs must therefore have provoked Fas–FasL-mediated CD4+ T-cell apoptosis through an indirect pathway.
In addition, transplant rejection occurs through recognition of foreign antigens presented by MHC molecules expressed on antigen-presenting cells, a process that can be mimicked by triggering T cells with CD3-specific mAb . We used anti-CD3 (OKT3) and anti-CD28 (CD28.2) mAbs, and recombinant mouse CD27L (Minneapolis, MN, USA) to stimulate T cells in a manner that partially mimics stimulation by antigen-presenting cells. We then checked FasL expression and apoptosis of CD4+ T cells. Our previous data showed an increase of FasL-positive cells and apoptotic CD4+ T cells by antigen presentation by T-cell receptor and co-stimulatory signals. However, the median fluorescence intensity of FasL and the apoptosis level varied by blood donor, incubation time, and the combinations of antibodies and recombinant protein (see Additional file 4).
In this paper, we demonstrated that CD70–CD27 interaction was involved in NSCs-induced CD4+ T cell apoptosis. Originally, CD27 is a cell surface glycoprotein belonging to the TNF receptor superfamily, which can provide stimulatory signals for both cell growth and apoptosis. CD70–CD27 interactions between most immune cells produce T cell expansion and the development of effector cytotoxic or memory T cells . On the other hand, it has been reported that CD27 can bind apoptosis-inducing factor (Siva 1), an intracellular mediator of apoptosis [33, 34], but the role of this interaction for the function of CD27 is yet to be resolved, because ligation of CD27 generally does not limit but rather contributes to the expansion of activated lymphocytes .
CD70 expressed on malignant cells showed novel function in immune escape . Human brain tumor cells, such as malignant glioma like or glioblastoma multiforme, express CD70 , and this CD70 – but not TNFα or FasL – initiated T-cell death through the receptor-dependent pathway . However, the exact mechanism of this process is not yet fully understood.
Levels of inhibition by both antibodies were otherwise incomplete, implicating the existence of other causes for apoptosis in addition to CD70–CD27 interaction. In CD70-mediated T-cell apoptosis, the role of Siva, a pro-apoptotic molecule, was identified, as well as soluble mediators such as transforming growth factor beta [32, 39]. We evaluated the expression of Siva protein using western blotting. Siva was increased at 48 hours in CD4+ T cells and the NSC co-culture system. We therefore think that, at least in our system, apoptosis was mainly induced by the FasL upregulation by CD27–CD70 ligation between NSCs and CD4+ T cells in the early phase (see Additional file 5).
We then examined cytokine profiles from the supernatant at various co-culture times (1, 3, 6, 12, 18, and 24 hours). Several cytokines (such as IL-1β, TNFα, IL-4, IL-10, IFNγ, IL-5, and IL-13) were shown to be negative in the co-culture periods. Moreover, IL-6 increased in a time-dependent manner. However, the IL-6 level is similar in the NSC-only culture group. In addition, the supernatant of the CD4+ T-cell-only culture group was shown to be negative for IL-6. Therefore, IL-6 might require NSC self-renewal and progenitor cell division and differentiation [40–42]. As in ESCs, lack of co-stimulation [9, 43] or participation of soluble mediators could play a role in T-cell immune escape. However, activation-induced cell death was less likely to play a role  since CD4+ T-cell apoptosis in our experiments reached its peak in 24 hours.
Finally, we have demonstrated that FasL expression on CD4+ T cells was significantly increased as a consequence of CD70–CD27 ligation. Antibody blocking experiments also confirmed that FasL expression on CD4+ T cells was CD70–CD27 dependent. NSCs therefore probably induce CD4+ T-cell apoptosis in two stages: CD70–CD27 ligation between NSCs and CD4+ T cells, which induces FasL expression on some CD4+ T cells, followed by Fas–FasL-mediated CD4+ T-cell apoptosis.
We demonstrated CD70–CD27 ligation to be an initiating step for NSC-induced CD4+ T-cell apoptosis. NSCs probably induce CD4+ T-cell apoptosis in two stages: CD70–CD27 ligation between NSCs and CD4+ T cells, which induces FasL expression on some CD4+ T cells, followed by Fas–FasL-mediated CD4+ T-cell apoptosis. Therefore, if it is possible to maintain persistent expression of CD70 using a gene delivery technique, this will be an exciting option to maintain immune escape in NSC transplantation.
Bovine serum albumin
Dulbecco’s modified eagle’s medium
Embryonic stem cell
Fluorescence-activated cell sorting
Major histocompatibility complex
Neural stem cell
Polymerase chain reaction
Tumor necrosis factor.
The authors gratefully acknowledge Sun Ha Paek (Department of Neurosurgery, College of Medicine, Seoul National University, Korea) and Jong-Hoon Kim (Division of Biotechnology, Korea University, Korea) for supply of the NSCs. This work was supported by the Ministry of the Knowledge Economy (grants 2009-67-10033838) and a grant from Hanwha Chemical Corporation (Project No. 0411–20070011).
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