International Immunology

International Immunology Advance Access published online on June 4, 2007
International Immunology, doi:10.1093/intimm/dxm033

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CD27–CD70 interactions sensitise naive CD4⁺ T cells for IL-12-induced T_h1 cell development

Michiel F. van Oosterwijk^1,2, Hedi Juwana^1,2, Ramon Arens^1,2, Kiki Tesselaar^1,3, Marinus H.J. van Oers², Eric Eldering¹ and René A.W. van Lier¹

¹ Department of Experimental Immunology
² Department of Hematology, Academic Medical Centre, Amsterdam, The Netherlands
³ Present address: Department of Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands

Correspondence to: Correspondence to: R. A. W. van Lier; E-mail: r.vanlier{at}amc.uva.nl

	Abstract

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Stimulation of CD27, a member of the tumour necrosis factor receptor family, by its ligand CD70 induces expansion of IFN secreting CD4⁺ and CD8⁺ T cells in vivo. We here analysed the mechanisms through which CD27 mediates this effect. CD27 co-stimulation induced cell division but did not directly instruct naive CD4⁺ T cells to differentiate into IFN-producing T_h1 cells. Rather, in concert with signals delivered through the TCR–CD3 complex, CD27 co-stimulation enhanced the T_h1-specific transcription factor T-bet and caused up-regulation of the IL-12Rbeta2 chain. Consequently, CD27-costimulated T cells yielded vast numbers of IFN-secreting cells in response to IL-12. Additionally, CD27 ligation induced a strong up-regulation of Bcl-x_L, but not of related anti-apoptotic molecules_. Thus, CD27–CD70 interactions may promote T_h1 formation by permitting naive T cells to respond to differentiation signals and by promoting survival of activated effector T cells.

Keywords: CD27, CD70, T cell differentiation, TNF-R family members

	Introduction

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Co-stimulatory signals transmitted through receptors that recognise cellular ligands are essential to initiate clonal expansion, survival and differentiation of naive T cells that have been activated by specific antigen. CD28, a molecule belonging to the Ig superfamily, appears to be a primary co-stimulatory receptor that, after ligation by either CD80 or CD86 on activated antigen-presenting cells (APC), prevents anergy, promotes cell cycle progression, survival and cytokine production (1). Furthermore, various members of the TNFR/tumour necrosis factor (TNF) family e.g. HVEM, CD27, OX40, 4-1BB and GITR appear to promote the generation and survival of effector T cells (2, 3). Based on their expression patterns, it has been postulated that these latter receptors may be engaged in a serial fashion, thereby providing means to accurately tune immune responses The abovementioned TNFR molecules use TRAF proteins to relay their signals and a prominent signalling outcome appears to be the up-regulation of anti-apoptotic Bcl-2-like molecules (2, 4, 5). However, also direct effects on proliferation and differentiation have been demonstrated for several of these receptors (6–9).

Both in human and mouse, CD27 is expressed on naive and memory-type T cells, antigen-primed B cells and subsets of NK cells (4). CD27 expression on lymphocytes is strongly enhanced after activation but lost on only chronically activated T cells. The CD27 ligand CD70 is transiently and stimulation-dependently expressed on T, B and dendritic cells (10). However, it has been recently demonstrated that CD70 is also constitutively expressed on APCs in the murine intestine (11).

We have generated transgenic mice that express CD70 under control of the human CD19 promotor. Consequently, all B cells from this mouse strain constitutively express the murine CD70 protein (12). The enhanced availability of CD70 in vivo leads to a CD27-dependent increase in numbers of both CD4⁺ as CD8⁺ T cells in secondary lymphoid tissues at young age (13). This expansion of T cells is due to an increased formation effector-type T cells, and intracellular staining revealed that IFN is a major cytokine produced by these cells (12)

The aim of this study was to analyse how CD27 signalling contributes to the enhanced formation of T_h1 cells. Our data show that CD27–CD70 interactions did not directly instruct naive CD4⁺ T cells to differentiate into IFN-producing cells but rather, through the up-regulation of the IL-12Rß2 chain, permitted these cells to respond to the T_h1-inducing cytokine IL-12. Furthermore, CD27 signalling specifically enhanced expression of Bcl-x_L, which will likely contribute to prolonged survival of effector cells in vivo.

	Methods

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Transfectants
Mock-transfected 3T3 and human CD70-transfected 3T3 (designated 3T70 in this study) mouse fibroblasts were cultured in culture medium consisting of IMDM (BioWhittaker, Verviers, Belgium), complemented with antibiotics [100 U ml^–1 sodium penicillin G (Brocades Pharma B.V., Leiderdorp, The Netherlands) and 100 µg ml^–1 streptomycin sulphate (Life Technologies, Paisley, Scotland)], 10% (v/v) heat-inactivated FCS (ICN Biomedicals, Meckenheim, Germany) and kept at 37°C in 5% CO₂. G418 (Invitrogen, Breda, The Netherlands) was added to the medium of the 3T70 cells to select for transfected cells.

Human CD4⁺ naive T-cell separation
PBMC were isolated from whole blood of healthy human donors by Ficoll density centrifugation. Subsequently, PBMC were re-suspended in medium (final concentration of 10 x 10⁶ cells per ml) and incubated for 30 min in the presence of CD8 mAb (clone CLB-T8/4, final concentration 10 µg ml^–1), CD19 mAb (clone CLB-CD19/1, final concentration 10 µg ml^–1), CD14 mAb (clone CLB-CD14/1, final concentration 5 µg ml^–1), CD16 mAb (clone CLB-CD16/1, final concentration 5 µg ml^–1), anti-class II mAb (clone E1, final concentration 10 µg ml^–1) and CD45RO mAb (clone UCHL-1, final concentration 5 µg ml^–1) at 4°C. After washing, cells were re-suspended (1.10⁷ cells per 900 µl medium) and 10 µl anti-mouse IgG dynal magnetic beads (Dynal) per 1.10⁶ cells were added. The cell suspension was incubated for 30 min at 4°C during constant rotating. By means of a magnetic particle concentrator, the cells that were labelled with the magnetic beads (i.e the unwanted fraction) were separated from the cells that remained in the supernatant. The purified fraction contained on average >95% CD4⁺CD45RA⁺CD27^bright, i.e. naive T cells.

Co-stimulation assay
Naive CD4⁺ T cells were incubated for 1 day in 24 wells coated with CD3 mAb (clone CLB-T3/3) (14) in the presence of either irradiated (7000 rad) 3T3 or 3T70 mouse fibroblasts. After this priming period, the cells were transferred to new wells and cultured in culture medium or in medium supplemented with either IL-12 or IL-4 (10 ng ml^–1, Strathmann) for an additional 5 days. To block CD27 ligation by 3T70 fibroblasts, CD70 mAb CLB-CD70/1 or CLB-CD70/2 (15) were added during the priming phase at a final concentration of 20 µg ml^–1. Quantification of cytokines produced in day supernatants was performed using DuoSet Elisa Kits (R&D systems, Abingdon, UK).

Carboxyfluorescein diacetate succinimidyl ester labelling
Cells were resolved in ice-cold PBS (2.10⁷ cells per ml) and an equal volume of carboxyfluorescein diacetate succinimidyl ester (CFSE) (final concentration 5 µM), Molecular Probes) in ice-cold PBS was added. Then, the cells were incubated for 10 min at 37°C under constant mixing. After the incubation, the cells were washed with culture medium and used for functional analysis.

Flow cytometry
Data acquisition was performed with FACSCalibur, and analyses were conducted using CellQuestPro software (BD Biosciences, San Jose, CA, USA). Cells were washed in PBS containing 0.01% (w/v) NaN₃ and 0.5% (w/v) BSA (PBA). Then fluorescent-labelled mAbs were added at concentrations according to manufacturer's instructions. The following mAbs were used : FITC-, PE- or allophycocyanin-labelled to CD4, CD8, CD62L, CCR5, (all BD PharMingen, San Diego, CA, USA), CD45RA (Beckman Coulter) and CD27 (clone CLB-CD27/1). For analysis of CCR7 expression, a three-step staining protocol was performed consisting of incubation with the CCR7 mAb (BD PharMingen), washing, incubation with biotinylated goat anti-mouse IgM (BD PharMingen), subsequent incubation with 10% (v/v) normal mouse serum (Sanquin, Amsterdam, The Netherlands) followed by incubation with streptavidin-PE (BD PharMingen).

For analysis of cytokine production, 1 x 10⁶ cells were first stimulated for 4 h at 37°C in a 24-well plate in 0.5 ml culture medium suplemented with phorbol 12-myristate 13-acetate (PMA, 2 ng ml^–1, Sigma-Aldrich, Zwijndrecht, The Netherlands), ionomycin (2 µM, Sigma-Aldrich, Zwijndrecht, The Netherlands) and brefeldin A (2 µg ml^–1, Sigma-Aldrich, Zwijndrecht, The Netherlands). Cells were washed, fixated with 4% (v/v) PFA and then the staining procedure was performed in 0.1% (v/v) saponine-containing PBA, using anti-IFN-, anti-IL-2, anti-IL-4, anti-IL-10 or anti-TNF- antibodies either FITC or PE labelled (all from BD Biosciences).

Gene expression measurements
After overnight priming of naive CD4⁺ T cells (1.10⁶ cells per sample), RNA was isolated employing the QIAgen RNA isolation kit. To measure the expression of apoptosis-related genes, we performed multiplex ligation-dependent probe amplification (MLPA) as described previously (16). In brief, RNA was reverse transcribed using a gene-specific probe mix and the cDNA was annealed overnight at 60°C to the MLPA probes and covalently linked by Ligase-65 at 54°C (MRC-Holland). Ligation products were amplified and fluorescently labelled by PCR. Samples were analysed on an ABI 3100 capillary sequencer (Applied Biosystems, Warrington, UK), and data analysed with Genescan and Genotyper (ABI), and further analysed with Microsoft Excel spreadsheet software. The sum of all peak data was set at 100% to correct for fluctuations in total signal between samples and individual peaks were calculated relative to the 100% value. Relative gene expression levels were calculated by subtracting the values obtained for unstimulated cells. The resulting datasets were imported in the TIGR Multiexperiment viewer version 2.2 for false colour representation (http://www.tigr.org/software/tm4).

Analysis of Bcl-x_L protein expression
Lysates were made from 1 x 10⁶-primed CD4⁺ T cells and western blots were performed according to standard protocols using 20 µg per lane. Anti-CD70 mAbs were added during the priming phase in certain samples as described above (co-stimulation assay). Anti-Bcl-x_L was purchased from Transduction Laboratories and the anti-ß-actin was purchased from Santa Cruz Biotechnology. After incubation with HRP-conjugated goat anti-rabbit, bound Igs were detected using ECL (Amersham Biosciences), according to manufacturer's instructions.

	Results

Top Abstract Introduction Methods Results Discussion References

 
CD27 co-stimulation enhances division of CD3-primed naive CD4⁺ T cells
We set out to analyse the consequences of CD27 ligation during the initial triggering of naive T cells. For this, we adapted the system described by van Stipdonk et al. (17) and stimulated naive CD4⁺ T cells with CD3 mAb in the presence of either mock-transfected or human CD70-transfected mouse 3T3 fibroblasts. After a priming period of 1 day, the cells were transferred to new wells and cultured for an additional 5 days in medium or in the presence of either IL-12 or IL-4 to stimulate T_h1 or T_h2 responses, respectively. A 24-h priming period with CD3 mAb did not initiate T-cell division as evidenced by the absence of CFSE dilution (Fig. 1). However, co-stimulation via CD70 during this period induced strong proliferation which was even enhanced in the presence of IL-12 but not IL-4 (not shown). Either cytokine was unable to synergise with CD3 mAb in the absence of CD70 co-stimulation. Addition of a blocking CD70 mAb (15) reduced proliferation to background levels confirming that the co-stimulatory effect on T-cell proliferation is dependent on CD70 expressed on the transfectants (Fig. 1).

View larger version (8K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1. CD27–CD70 interactions promote division of TCR/CD3-stimulated naive T cells. Naive CD4+ T cells were labelled with CFSE and incubated on either mock or human CD70-transfected fibroblasts in the presence or absence of a stimulatory CD3 mAb. Where indicated, a blocking CD70 mAb was added during this priming period. After 24 h, the T cells were removed from the fibroblasts and cultured in fresh culture medium supplemented or not with IL-12 for an additional 5 days. Cells were analysed on a FACSCalibur. The histograms are representative for experiments performed with five different donors.

 
To monitor phenotypic changes, we performed flow cytometric analysis. The naive CD4⁺ T cells remained CD45RA⁺, CD27⁺, CCR7⁺, CCR5^– and CD62L⁺ when primed with CD3 mAb without co-stimulation. However, in the presence of the CD70-expressing fibroblasts, the cells became CD62L^–, CD45RA^– and CCR7^–, indicative of the formation of effector cells (not shown).

CD70 triggering primes naive CD4⁺ T cells for T_h1 development
To determine potential effector functions of the expanded naive T cells, we analysed PMA/ionomycin-induced expression of IFN and IL-4. No induction of cytokine-forming cells was found in the cultures that only contained undivided T cells. Further, although cells proliferated vigorously in response to CD70 co-stimulation (Fig. 1), no significant formation of cytokine-producing cells was detectable in these cultures in the absence of differentiation-inducing cytokines (Fig. 2A). However, when the cells were primed in the presence of CD70-expressing fibroblasts and thereafter cultured in IL-12, a clear population of IFN-producing T cells emerged. For IL-2 and TNF-a production similar data were obtained (not shown). Corroborating these findings, IFN was only detected at considerable concentrations in supernatants of 3T70 primed, IL-12 cultured T cells (Fig. 2B). The formation of IFN-producing cells and secretion of IFN could be blocked with CD70 mAb (Fig. 2). Thus, CD27 signalling during priming contributes to the formation of IL-12-responsive CD4⁺ T cells.

View larger version (40K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2. CD27–CD70 interactions promote Th1 differentiation. (A) naive CD4+ T cells were stimulated as described in the legend of Fig. 1. At the end of culture, the cells were stimulated with a combination of PMA/ionomycin in the presence of brefeldin A. Intracellular cytokine content was measured using specific antibodies. Representative histograms of one donor out of four tested is shown. (B) Secretion of IFN in the supernatants of the T cells stimulated as described in the legend of Fig. 1. The error bars represent standard deviation of four independent experiments.

 
In contrast, the addition of IL-4 during the outgrowth of the activated cells did not lead to the formation of IL-4 (or IL-10, not shown) producing T_h2 cells either in the absence or presence of CD70 co-stimulation (not shown). To exclude a possible kinetic difference in the induction of T_h1 versus T_h2 responses, we extended the priming period. However, also prolonging the priming period up to 3 days did not lead to the formation of IL-4-producing effector cells (data not shown). So in the system used here, CD27–CD70 interactions exclusively facilitate T_h1 development.

CD27 co-stimulation induces T-bet and IL-12Rß2 expression in naive T cells
The transcription factor T-bet plays a central role in the induction of T_h1 immune responses (18, 19). Part of the effect of T-bet might be generated through the induction of IL-12Rß2, which is essential for the formation of an active IL-12R (20). Since we observed enhanced IL-12 responsiveness after priming with CD3 mAb in the presence of CD70 transfectants, we studied the regulation of expression of both T-bet and the IL-12Rß2 chain after the naive T-cell priming.

To measure the level of T-bet mRNA expression, we performed a quantitative PCR reaction (light-cycler reverse transcription–PCR) in comparison with a housekeeping gene (GAPDH). Figure 3A shows that the expression of T-bet is up-regulated after priming by CD3 mAb with 3T70 fibroblasts. The addition of a blocking CD70 mAb showed that this effect is dependent on CD27 signalling. No effect of CD27 signalling on the expression of GATA-3, a transcription factor implicated in T_h2-cell formation, was observed. The priming of naive CD4⁺ T cells with CD3 mAb and mock transfectants led to a slight enhancement of GATA-3 (not shown). In line with the observed increase in T-bet expression and IL-12 responsiveness, CD27 signalling indeed led to an enhanced expression of IL-12Rß2 (Fig. 3B).

View larger version (26K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 3. CD27 triggering induced the up-regulation of T-bet and IL-12Rb2. (A) naive CD4+ T cells were stimulated for 24 h in the presence or absence of CD27 triggering. Thereafter, RNA was harvested and T-bet levels were determined by real time RT–PCR. (B) Naive CD4+ T cells were stimulated for 24 h in the presence or absence of CD27 triggering. Thereafter, IL-12Rb2 expression was measured with a specific antibody.

 
CD27 ligation specifically up-regulates Bcl-x_L expression
In addition to the aforementioned effects on expansion and differentiation, TNFR family members are known to directly affect survival capacities of activated T cells (3, 4, 21). Therefore, we tested whether CD27 signalling might also have a direct influence to antagonise apoptosis. To this end we made use of MLPA analysis (16) and measured changes in the expression levels of 35 apoptosis-related genes. Among these genes, only the expression of anti-apoptotic Bcl-x_L increased in a fashion that clearly depended on CD70 co-stimulation (Fig. 4A). Western blotting confirmed this effect at the protein level (Fig. 4B). Both at the mRNA and protein level, the expression of Bcl-x_L could be prevented by addition of antagonistic CD70 antibodies (anti-CD70/1 and anti-CD70/2). These results strongly suggest that in addition to effects on differentiation, CD27 signalling mediates increased survival via the specific induction of Bcl-x_L.

View larger version (17K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 4. CD27–CD70 interactions up-regulate Bcl-xL expression. Naive CD4+ T cells were stimulated for 24 h in the presence or absence of CD27 triggering, and in presence or absence of antagonistic anti-CD70 mAbs, as indicated. (A) RNA was harvested and MLPA analysis was performed as described in Methods. Relative expression levels are indicated in false colour in relation to unstimulated cells. Bcl-xL expression is boxed to highlight its specific induction upon CD27 signalling. (B) NP-40 protein lysates were made and Bcl-xL expression was determined by western blotting. Under non-proliferating conditions, protein yields varied somewhat as evidenced by distinct levels of ß-actin. Two separate antagonistic anti-CD70 mAbs (designated aCD70-1 and aCD70-2) gave partial and full inhibition of Bcl-xL induction.

 

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Results presented in this study show that CD27 signalling may stimulate the formation of T_h1 cells via (i) promotion of T-cell division, (ii) induction of T-bet which up-regulates IL-12Rß2 and thus confers IL-12 responsiveness and (iii) up-regulation of Bcl-x_L which will promote survival of expanded cells.

A direct effect of TNFR family proteins on cellular division is not unprecedented since these effects have been shown for 4-1BB, OX40 and also for CD27 signalling in vivo (6, 8). Importantly, Song et al. (7) recently showed that OX40 signalling via the activation of PI3K and PKB induces the sustained expression of survivin, thereby directly promoting cellular division. Although up-regulation of T-bet and Bcl-x_L was observed after 24 h of activation, in the MLPA analysis we did not observe an effect on CD27 ligation on survivin during this culture period. Yet, after 3 days of culture survivin expression was found, it is unclear whether this was a direct result of CD27 triggering or rather the consequence of additional signals that influence gene expression in activated T cells. It should be noted that there appears to be a paradox between studies performed in CD27-deficient mice and experiments in which CD70 ligand is supplied. In CD27-deficient mice, the effect of CD27 on the size of the antigen-activated T-cell pool could be attributed to increased survival rather than enhanced division (5). Likely, stimulation of CD27 via CD70 transfectants, soluble ligand or transgenically expressed CD70, gives a strong ligation of the receptor. In many experimental infection models, such as the influenza infection model in which the CD27-deficient animals have been analysed (22). CD70 expression is very low. Pathogens that give a strong and persistent expression of CD70 have yet to be identified in the mouse, but in humans CMV is an attractive candidate since this virus is associated with the vast formation of CD27^– T cells that form as a consequence of CD27–CD70 interaction (23).

To generate a T_h1 immune response, naive CD4⁺ T cells have to be activated through TCR and co-stimulatory receptors and moreover receive signals that induce differentiation. Mullen et al. (19) proposed a model in which IL-12 responsiveness of T cells is dependent on the activation of T-bet, a T_h1-specific transcription factor. T-bet expression will lead to up-regulation of the IL-12Rß2 subunit, which subsequently will enable the formation of the active IL-12R. Importantly, expression of T-bet will also facilitate transcription of the IFN locus by enabling accessibility for transcription factors (STAT4) via modification of the chromatin structure (24). These changes in chromatin structure will remain permanent after at least four rounds of cell divisions and consequently the cell will become a committed T_h1 cell. The positive effect of CD27 signalling on up-regulation of T-bet expression described here suggests a supportive role of CD27–CD70 interaction in the formation of a T_h1 cells.

It was recently demonstrated that CD27 couples to both canonical and non-canonical NF-kB signalling pathways (25). At this moment, it is unclear if the differential effects we observe on T_h1 cell formation, i.e. promotion of division, sensitisation for differentiation and up-regulation of survival promoting factors, can be attributed to either pathway. Regardless, the influence of CD27 on these various pathways makes this receptor an attractive target to boost immune responses. The recent observation that soluble CD70 works as a potent in vivo adjuvant that improves cytotoxic CD8⁺ T-cells responses via increased division and survival of antigen-primed cells may be taken in support for this notion (8).

	Acknowledgements

 
M.F.v.O. and H.J. were supported by KWF grant AMC 2000-2148.

	Abbreviations

 

APC, antigen-presenting cell

CFSE, carboxyfluorescein diacetate succinimidyl ester

MLPA, multiplex ligation-dependent probe amplification

PMA, phorbol 12-myristate 13-acetate

TNF, tumour necrosis factor

	Notes

 
Transmitting editor: T. Kipps

Received 19 October 2005, accepted 26 February 2007.

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