International Immunology

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International Immunology, Vol. 12, No. 11, 1547-1552, November 2000
© 2000 Japanese Society for Immunology

Role of Tec kinase in nuclear factor of activated T cells signaling

Wen-Chin Yang², Marguerite Ghiotto, Rémy Castellano, Yves Collette, Nathalie Auphan¹, Jacques A. Nunès and Daniel Olive

INSERM U119, Institut d'Immunologie et de Cancérologie de Marseille, Université de la Méditerranée, 27 Bd Leï Roure, 13009 Marseille, France
¹ Centre d'Immunologie INSERM-CNRS de Marseille-Luminy, 13288 Marseille, France

Correspondence to: J. A. Nunès or D. Olive

	Abstract

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The Tec protein kinase family includes Btk, Itk, Tec, Rlk and Bmx, which are critically involved in signals mediated by various cytokines and antigen receptors. Btk mutations cause severe immunodeficiencies, with defective B cell function. In T cells, Tec regulates cytokine production. However, the downstream targets of these Tec kinases are poorly defined. Here we report that overexpression of Tec in T cells can regulate gene transcription through the nuclear factor of activated T cells (NF-AT). Using different reporter gene constructs, we establish that Tec in transfected T cells dramatically induced NF-AT-dependent gene transcription, which was prevented by a dominant-negative mutant of NF-AT or by the immunosuppressive drug cyclosporin A. Tec appears to regulate NF-AT nuclear import. In addition, Tec influences cytoplasmic free calcium increase. Taken together, our results identify NF-AT as a major downstream target of Tec kinases that is critically involved in transcriptional gene regulation. These observations highlight signaling pathways regulated by Tec kinases and provide new pharmacological targets to regulate immune functions.

Keywords: signal transduction, T cells, Tec family kinases, transcription factors

	Introduction

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Over the past decade, two major families of cytoplasmic protein tyrosine kinases (PTK), Src and Syk have been implicated in initiating antigen receptor signaling (1). A third PTK family, Tec, has emerged recently as a critical regulator in various cytokines and antigen receptors signaling (2). Three Tec family members, Itk, Rlk and Tec, are expressed in T cells and can be activated upon TCR ligation (3–5). Following the fact that Tec family kinases activation is an early event during TCR triggering, identification of Tec family PTK downstream targets such as transcription factors becomes an important field to investigate. The PTK Tec is a powerful activator of the transcription of cytokine genes such as IL-2 or IL-4 (5,6). Thus, we used this PTK Tec to test the nature of the transcription factors activated in T cells by Tec family members. It has been reported that the nuclear localization of NF-AT2 is affected in Itk-deficient mice (7). Here, we show that the PTK Tec potentiates essentially NF-AT transcription activity by at least regulating NF-AT nuclear import.

Jurkat T cells and RBL-2H3 mast cell line (ATCC, Rockville, MD; CRL-2256) were maintained in RPMI 1640 medium supplemented with 10% FCS, penicillin, streptomycin and glutamine. PCDNAflagTec, containing a wild-type full-length murine Tec IV cDNA, and pCDNAflagTeckd, a Tec kinase-dead version tagged with the FLAG epitope, were previously described (5). Teckd is the kinase-dead version of Tec with a point mutation at the ATP-binding site of Tec corresponding to amino acid 397 (K E). prCD2flagTec was constructed by in-frame subcloning the PCR products of full-length Tec to the downstream extracellular and transmembrane domains of the rat CD2 molecule into the pCDNA3 expression vector. prCD2flagTeckd was the kinase-dead version of prCD2flagTec. The pIL-2-Luc construct containing the human IL-2 promoter (nucleotides –340 to +57) fused to the firefly luciferase reporter gene is a gift from Dr E. Verdin. The pß-actin-RLuc reporter gene composed of ß-actin promoter fused with Renilla luciferase was described previously (5). pNF-AT, pAP-1 and pNF-B-Luc constructs containing trimeric NF-AT, pentameric AP-1 or trimeric NFB sites fused with minimal promoter followed by firefly luciferase have been described previously (8–10). The dominant-negative NF-AT construct was described previously (11). The full-length NF-ATc1 cDNA subcloned into the pEGFP-C1 vector (Clontech, Palo Alto, CA) to give NF-ATc1–green fluorescent protein (GFP) was the kind gift of Dr E. McKenzie (Yamamouchi Research Institute, Oxford, UK).

The mAb 289 recognizes CD3 chain of the TCR and was used at 10 µg/ml. The anti-FLAG mAb (M2) was purchased from Sigma (St Louis, MO). The anti-rat CD2 mAb (OX34) was the kind gift of Dr D. Cantrell (ICRF, London, UK). Polyclonal antibodies against murine Tec protein were as previously described (5). Goat anti-mouse IgG antiserum conjugated with FITC (GAM–FITC) and GAM conjugated with Texas Red (GAM–TR) were purchased from Beckman-Coulter (Marseille, France) and Molecular Probes (Eugene, OR) respectively. Phorbol myristate acetate (PMA) and cyclosporin A (CsA) were purchased from Sigma and Calbiochem (San Diego, CA) respectively.

Jurkat T cells (10⁷) were electroporated at 960 µF and 250 V using a BioRad (Hercules, CA) Gene Pulser with the various reporter constructs together with plasmids containing Tec or its kinase-dead mutant as indicated in figure legends. The cells were incubated for 2 h, then treated or not for 6 h with PMA at 50 ng/ml or PMA plus CD3–TCR mAb (289; 10 µg/ml) either in the presence or absence of CsA (0.3 ng/ml). PMA treatment induces cytomegalovirus-driven expression of the Tec in Jurkat T cells and it should be noted that PMA could not significantly influence Tec kinase activity (data not shown). The sensitivity of anti-Flag immunoblot does not permit to detect overexpression of Tec kinase in non-treated PMA Jurkat cells. However, transfections of Tec kinase constructs increase IL-2 promoter activity 2- or 3-fold in non-treated Jurkat cells (data not shown). The cells were harvested by centrifugation. The supernatants were used to quantify cytokine production with an IL-2 ELISA kit according to the manufacturer's instructions (Beckman-Coulter). Cell pellets were washed and lysed. Then Bradford reagent (BioRad) was used to quantify protein concentrations. Total lysate (30 µg) was subjected to SDS–PAGE electrophoresis. Following transfer to a PVDF membrane (Millipore, Bedford, MA), the membrane was blotted with antibodies to determine Tec expressions.

Cell lysate (10 µg) was subjected to the dual luciferase reporter assay according to the manufacturer's instruction (Promega, Madison, WI). The efficiency of transfection was corrected by the activity of firefly luciferase normalized by that of Renilla luciferase. The fold induction was obtained by the fold induction of each corrected value over that obtained in the absence of any treatment with the empty vector (mock) condition. Histograms with error bars indicate the arithmetic mean + SD of fold inductions from independent experiments.

RBL-2H3 cells (2x10⁷) were electroporated using a BioRad Gene Pulser at 960 µF and 330 V, with 5 µg of NF-ATc1–GFP and 10 µg of empty vector (pCDNA3), pCDNAflagTec or prCD2flagTec. After plating onto glass coverslips, cells were allowed 5 h recovery and washed 2 times with PBS. Cells were fixed in 3% paraformaldehyde for 20 min at room temperature, permeabilized in 0.1% Triton X-100 for 5 min and processed for indirect immunofluorescence. Primary antibody anti-FLAG mAb was used at 0.5 µg/ml and secondary antibody GAM–TR was diluted 1:600 in PBS containing 10% FCS (60 min each incubation at 20°C). Cells were washed 3 times with PBS and coverslips mounted on glass slides onto a drop of Mowiol solution. Cells were analyzed with a TCN-NT confocal fluorescence microscope (Leica, Heidelberg, Germany). Co-expression of Tec was confirmed by immunostaining using anti-Flag mAb and by Western analysis of whole-cell lysate using polyclonal antibodies against Tec. The nuclear translocation was scored and, as found in one representative experiment out of three, one could find three distinct patterns, complete NF-ATc1 nuclear translocation which was only found in Tec transfected cells, predominant nuclear NF-ATc1 nuclear translocation with weak cytosolic staining respectively 40.6% in Tec transfected cells and 12.8% in cells transfected with empty plasmid and finally cytosolic localization.

Jurkat T cells (10⁷) were electroporated at 960 µF and 250 V using a BioRad Gene Pulser with prCD2, prCD2flagTec or prCD2flagTeckd. The cells were incubated for 2 h and then treated for 12 h with PMA at 10 ng/ml. The cells were incubated with 5 µM Indo-1-AM (Molecular probes, Eugene, OR) for 45 min and then transfected cells were incubated at 37°C for 3 min with anti-rat CD2 mAb (10 µg/ml). Cell response was monitored by a flow cytometer (FACS Vantage; Becton Dickinson, San Jose, CA). Ca_i²⁺ mobilization was monitored for 512 s. Time 0 corresponds to the addition of 20 µg/ml GAM–FITC. Expression levels of transfected rat CD2 molecules were analyzed after 15 min by using FITC analysis parameters.

Overexpression of Tec in Jurkat T cells increases the activity of IL-2 promoter elements, especially NF-AT. T cell activation can induce cytokine expression including IL-2. We showed that Tec kinase activity can regulate the basal activity of IL-2 promoter and further potentiates TCR-mediated signal transduction (5) (Fig. 1A). In accordance, we are also able to detect production of endogenous IL-2 in transfected Jurkat T cells induced by Tec overexpression (Fig. 1B). Tec and its kinase-dead version (Teckd) were expressed at a comparable level in all transfections (Fig. 1C). Moreover, Tec kinase can potentiate a strong IL-2 promoter activity mediated by PMA + ionomycin. Overexpression of the kinase-dead version of Tec does not affect IL-2 promoter activity in PMA + ionomycin activated Jurkat cells (data not shown). The cis-acting elements in the IL-2 promoter bind nuclear factors, including AP-1, NF-AT and NF-B (12). The promoter of the IL-2 gene has provided a model system to investigate the nature of Tec nuclear factor targets. Reporter constructs containing multimers of either element are responsive to T cell activation. To investigate the role of Tec family kinases in regulating cytokine expression, we co-transfected Jurkat cells with these reporter constructs (pAP-1-Luc, pNF-AT-Luc or pNFB-Luc) together with Tec-encoding vectors and luciferase activity was determined (Fig. 1D). Overexpression of Tec has no significant effect on AP-1 or a minor effect on NF-B-driven transcription. Similar results were obtained using 5-fold lower PMA concentration (10 ng/ml) (data not shown). However, Tec can strongly induce NF-AT enhancer activity (Fig. 1D). The kinase-dead version of Tec (Teckd) is unable to influence NF-AT induction. Thus, Tec-mediated NF-AT activity requires Tec kinase activity.

View larger version (16K): [in this window] [in a new window]   Fig. 1. Overexpression of Tec in T cells increases the activity of IL-2 promoter elements, especially NF-AT. Jurkat T cells were transfected by electroporation and treated with PMA for 6 h. Reporter plasmid (20 µg) was co-transfected with an empty vector (mock) (15 µg), FLAG-tagged wild-type Tec (Tec) or its kinase-dead mutant (Teckd) plus pßactin-RLuc (5 µg). Data shown are the average of three experiments ± SD. (A) Reporter plasmid containing luciferase driven by the full-length IL-2 promoter was assayed. The fold induction corresponds to the fold induction over that obtained in the empty vector condition. (B) The media were further quantified for endogenous IL-2 production using IL-2 ELISA kit. (C) A representative experiment is analyzed for Tec expression. Total lysate (30 µg) was subjected to SDS–PAGE electrophoresis. Following transfer to PVDF membrane, the membrane was blotted with anti-FLAG mAb to determine exogenous Tec expression levels. Mobilities of mol. wt standards are indicated (kDa). (D) Reporter plasmids containing luciferase driven by the individual transcription factor binding sites (AP-1, NF-AT and NF-B) were assayed. Using anti-murine Tec antibodies, similar levels of exogenous Tec expression are detectable for the different transfection conditions (data not shown). Relative fold induction refers to the fold induction over that obtained in PMA-treated mock condition for each individual transcription factor binding sites.

 
A dominant-negative form of NF-AT or CsA can block Tec-mediated IL-2 promoter activation. A dominant-negative NF-AT protein has been described as a strong inhibitor of all NF-AT family members (11). By inhibiting NF-AT transcription activity, dominant-negative NF-AT acts as an inhibitor of IL-2 expression. To evaluate the impact of Tec on IL-2 promoter activity, we repeated pIL-2 and NF-AT reporter assays with this dominant-negative NF-AT. Dominant-negative NF-AT could effectively inhibit the activation of pIL-2 and NF-AT reporter (Fig. 2A). Thus, dominant-negative NF-AT inhibits the endogenous activity of NF-AT induced by Tec and this NF-AT activity is necessary for Tec-mediated IL-2 promoter activation. The immunosuppressive drug CsA can inhibit cytokine expression such as IL-2 by inhibiting calcineurin, a serine/threonine phosphatase, which can dephosphorylate cytoplasmic NF-AT. Dephosphorylated NF-AT translocates into the nucleus where it regulates NF-AT-dependent transcription. Inhibition of calcineurin by CsA can block NF-AT activation (13). Tec kinase activity potentiates TCR-mediated up-regulation of IL-2 transcriptional activity (5). Furthermore, Tec potentiates TCR-mediated up-regulation of NF-AT transcriptional activity (Fig. 2b). Tec influences NF-AT transcription activity induced by stimulation of other membrane receptors such as CD28 (data not shown). In Fig. 2(B), we showed that CsA could inhibit both IL-2 promoter activities induced by Tec overexpression in the absence or presence of TCR stimulation. Under the same conditions, NF-AT activity is also affected by CsA treatment. Using these NF-AT inhibitors, these results imply that Tec regulates IL-2 expression by NF-AT activation

View larger version (26K): [in this window] [in a new window]   Fig. 2. Dominant-negative NF-AT or CsA inhibits Tec-mediated activation of IL-2 promoter elements. Jurkat cells were transfected as described in Fig. 1. Reporters driven by the IL-2 promoter (pIL-2 Luc) or the NF-AT binding site were assayed. Data showed the condition using FLAG-tagged wild-type Tec. (A) Jurkat cells were co-transfected or not with plasmid encoding for a dominant-negative form of NF-AT (0.5 µg) (dnNF-AT). (B) Transfected cells were stimulated or not with anti-CD3–TCR antibodies (289) at 10 µg/ml in combination with CsA at 0.3 ng/ml. Data shown are the average of three experiments ± SD.

 
Tec overexpression induces NF-ATc1–GFP nuclear import. NF-AT family members appear to be controlled primarily at the level of nuclear localization (14). Constitutive nuclear expression of NF-AT in our Jurkat T cell model eliminates the ability to study endogenous NF-AT nuclear import (data not shown). To study the capacity of Tec to induce NF-AT translocation to the nucleus, a NF-ATc1–GFP construct transfected in a basophilic cell line (RBL-2H3) has been used as previously described (15). In this context, RBL-2H3 cells were transfected with NF-ATc1–GFP together with Tec. The montage of confocal microscope images in Fig. 3(A) shows that NF-ATc1–GFP is excluded from the nucleus in RBL-2H3 cells co-transfected with an empty vector (mock). Upon transfection with Tec construct, NF-ATc1–GFP is accumulated in the nucleus. Tec family member activation requires generally an anchoring at the plasma membrane (16). We generated a membrane-targeted version of Tec (rCD2Tec), expecting to potentiate its kinase activity. However, Tec or rCD2Tec presents a similar kinase activity in transfected COS cells (5). rCD2Tec overexpression, like Tec, is able to potentiate cytokine promoter activity (data not shown). Here, we report that this membrane-targeted version of Tec is also able to induce a NF-ATc1–GFP nuclear translocation. Expression of Tec and its membrane-targeted version (rCD2Tec) were also detectable by immunoblots in all transfections (Fig. 3B). Thus, Tec can be involved in the control of NF-AT nuclear localization. These results are consistent with recent work showing that the magnitude of NF-ATc nuclear localization is impaired in Itk-deficient T cells (7). This suggests that upon overexpression, they are both able to induce NF-AT translocation towards the nucleus. Itk is another member of Tec family kinases. However, a kinase-dead version of Tec is also able to induce NF-AT nuclear import in RBL-2H3, supporting the fact that the kinase activity is not required for NF-AT translocation (data not shown). This suggests that other functional domains of the Tec kinase are involved in lymphocyte signaling. In parallel, Tec is implicated in calcium mobilization. NF-AT transcription factors are imported into the nucleus in response to calcium signals induced by plasma membrane receptors (17). Other members of Tec kinase family such as Btk, Itk and Rlk are reported to influence Ca²⁺ responses (18–22). Using the membrane-targeted version of Tec (rCD2Tec) or its kinase-dead mutant (rCD2Teckd), we tested whether Tec could induce Ca²⁺ mobilization in T cells. By cross-linking with anti-rat CD2 mAb, membrane-targeted Tec but not membrane-targeted kinase-dead Tec and control construct (rCD2) can increase Ca²⁺ mobilization in transfected Jurkat T cells (Fig. 4, right row). Expression levels of transfected molecules were detected by FACS flow cytometry and were expressed at a comparable level in all transfections (Fig. 4, left row). This result may explain why Tec can activate NF-AT activity that is tightly controlled by the Ca²⁺/calmodulin-dependent calcineurin pathway.

View larger version (32K): [in this window] [in a new window]   Fig. 3. Tec overexpression induces NF-AT–GFP nuclear localization. RBL-2H3 cells were transfected with NF-ATC1–GFP and flag-tagged Tec (Tec), rCD2-flag-tagged Tec (rCD2Tec) or empty pCDNA3 vectors and analyzed by confocal microscopy as described in supplementary material. (A) Cells were fixed and stained with anti-FLAG antibody plus GAM–TR. Tec expression is visualized by red fluorescence and NF-AT by green fluorescence. Solid bar corresponds to 10 µm. Tec expression is also detectable in anti-Tec immunoblots. (B) Lysates of untransfected RBL-2H3 cells (Ctrl) or transfected cells from the experiment shown were resolved by SDS–PAGE, transferred to PVDF membrane and immunoblotted with anti-Tec antiserum. Arrows indicate rCD2flagTec and flagTec. Mobilities of mol. wt standards are indicated (kDa).

 

View larger version (52K): [in this window] [in a new window]   Fig. 4. The membrane-targeted form of wild-type Tec can mobilize cytosolic free calcium after cross-linking. Jurkat cells transfected with plasmids encoding prCD2 (upper panel), prCD2Tec (rCD2Tec) (middle panel) and prCD2Tec kinase-dead mutant (rCD2Teckd) (lower panel) were loaded with Indo-1 AM. Transfected cells were stimulated by anti-rat CD2 mAb plus GAM–FITC. Calcium mobilization was monitored for 512 s using a flow cytometer. Indo-1 fluorescence ratio (violet/blue) represented the intracellular calcium level (right panels). Expression levels of transfected molecules were detected by FACS flow cytometer. The shaded area shows transfected cells in contrast to untransfected cells shown by the blank area (left panels). Data are representative of two independent experiments.

 
These results are consistent with a model where Tec acts on cytokine production by NF-AT induction at least at the level of nuclear localization. An explanation would be that Tec could regulate a Ca²⁺ rise associated with NF-AT translocation that would finally contribute to NF-AT enhancer activation. Differential gene pattern expression can be induced by amplitude modulation of Ca²⁺ signals, which are responsible for transmitting information to the nucleus (23). The identification of NF-AT proteins as targets for Tec kinase pathways could have implications for the control of T cell responses.

	Acknowledgments

 
This work was supported by the Institut National de la Santé et de la Recherche Médicale, Ligue Nationale de Lutte Contre le Cancer and Association pour la Recherche Contre le Cancer. We thank Drs D. A. Cantrell, H. Turner, C. Bebbington, S. Desiderio, J. Ihle, E. Verdin and S. Guerder for kindly providing reagents and helpful discussions, J. R. Galindo for flow cytometry analysis, D. Isnardon for confocal microscopy analysis, Dr P. Chavrier for his expert help in the interpretation of confocal microscopy images, Dr C. Mawas, J. Imbert and Mrs C. Lipcey for their critical review of this manuscript, and their colleagues for their excellent technique assistance.

	Abbreviations

 

CsA cyclosporin A

GAM goat anti-mouse IgG

GFP green fluorescent protein

NF-AT nuclear factor of activated T cells

PMA phorbol myristate acetate

PTK protein tyrosine kinase

TR Texas Red

	Notes

 
² Present address: Department of Pathology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA

Transmitting editor: L. Moretta

Received 11 April 2000, accepted 21 July 2000.

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