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The Journal of Immunology, 1998, 161: 3416-3420.
Copyright © 1998 by The American Association of Immunologists

Impaired TCR-Mediated Apoptosis and Bcl-XL Expression in T Cells Lacking the Stress Kinase Activator SEK1/MKK4

Hiroshi Nishina*,§,¶, Laszlo Radvanyi§,¶, Kaliannan Raju§,¶, Takehiko Sasaki*,§,¶, Ivona Kozieradzki*,§,¶ and Josef M. Penninger1,*,§,¶

* Amgen Institute, University of Toronto, Ontario, Canada; and {dagger} Ontario Cancer Institute, and {ddagger} Departments of Medical Biophysics and Immunology, University of Toronto, Ontario, Canada; and § Ontario Cancer Institute, Departments of Medical Biophysics and Immunology, Ontario, Canada.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
The dual specificity kinase SEK1 (MKK4) is a direct activator of stress-activated protein kinases (SAPK/JNK) in response to environmental stresses or mitogenic factors. We show in Sek1-/-Rag-/- chimeric mice that a Sek1 null mutation augments the susceptibility of peripheral T cells to TCR/CD3 religation-induced apoptosis. Sek1-/- T cells failed to induce expression of the death suppressor Bcl-XL in response to Ag receptor activation. The Sek1 mutation did not alter the induction of apoptosis in response to etoposide, cisplatinum, Adriamycin, and {gamma}-irradiation. Moreover, we show that CD3{epsilon} activation alone leads to SEK1 activation in Sek1+/+ T cells. These results suggest that SEK1 transduces cellular survival signals during T cell stimulation.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
During the development of multicellular organisms, cell fate decisions determine whether cells undergo proliferation, differentiation, or apoptosis. Stress-activated protein kinases/c-Jun NH2-terminal kinases (SAPK/JNK)2 are activated in response to many cellular and environmental cues and relay stress signals to nuclear transcription factors (1, 2). SAPKs/JNKs are activated by the phosphorylation of tyrosine and threonine residues in a reaction that is catalyzed by the dual specificity kinase SEK1 (also known as MKK4 and JNKK) (3, 4, 5, 6).

It has been proposed that the SEK1->SAPK/JNK signaling cascade is a common pathway required for the induction of apoptosis in response to many types of cellular stresses, including UV and {gamma}-irradiation, protein synthesis inhibitors, high osmolarity, toxins, ischemia/reperfusion injury in heart attacks, heat shock, ceramide, inflammatory cytokines such as TNF-{alpha}, or cytokine deprivation (7, 8, 9, 10). Besides activation of the SAPK/JNK signaling cascade in response to stress, SEK1 and SEK1-mediated SAPK activation also regulate proliferation and IL-2 production of T cells following CD28 costimulation (11, 12) and participate in signals in response to growth factors, G proteins, and phorbol esters (2, 11, 13, 14, 15). Moreover, we have shown previously that SEK1 provides a survival signal in thymocyte development (16).

In this work, we report in Sek1 gene-deficient chimeric mice that primary activated peripheral T cells exhibit enhanced susceptibility to apoptosis in response to TCR/CD3{epsilon} religation. The Sek1 mutation did not alter the induction of apoptosis in response to cisplatinum, Adriamycin, {gamma}-irradiation, and etoposide. Sek1-/- T cells failed to induce expression of the death suppressor Bcl-XL in response to Ag receptor activation. These results suggest that SEK1 is required to transduce cellular survival signals during T cell stimulation.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Mice

The generation of ES cells homozygous for the Sek1 mutation and Sek1-/- and Sek1+/+ somatic chimeras using Rag2-/- blastocyst complementation has been described (16). T cells from Sek1-/-Rag2-/- mice were tested for the Sek1 mutation using PCR (12). If not otherwise stated, all mice used for experiments were between 6 and 10 wk of age. Mice were kept in accordance with guidelines of Canadian Medical Research Council.

TCR religation on primary activated T cells

Splenic T cells (4 x 106) were cultured in 24-well Costar plates (Fisher Scientific) in 2 ml {alpha}MEM medium (supplemented with 2 mM glutamine, 1 mM sodium pyruvate, 15 mM HEPES, 10-5 M ß-mercaptoethanol, and 10% FCS) for 48 h at 37°C. Cells were activated with soluble anti-CD3{epsilon} mAb (clone 145-2C11; 3 µg/ml) and exogenous murine rIL-2 (25 U/ml; Genzyme, Cambridge, MA) (17). After 48 h, activated T cells were harvested using Lympholyte-M and washed, and the remaining B cells were removed using anti-IgG magnetic beads (10:1 bead:cell ratio; Cedarlane Laboratories, Hornby, Ontario, Canada). Purified activated T cells (0.5 x 106/ml) were cultured for 4 h in {alpha}MEM containing 50 U/ml of murine rIL-2 (Genzyme), and replated in 96-well plates containing 3 µg/ml plate-bound anti-CD3{epsilon} (clone 145-2C11) or plate-bound anti-TCRß (clone H57.597) and rIL-2 (50 U/ml) in the presence or absence of anti-CD28 (1 µg/ml; clone 37.51, hamster IgG). Cell viability and apoptosis were assessed 48 h after religation using eosin staining to determine total live and dead cell numbers, the chromogene 7-aminoactinomycin D (7AAD) (1 µg/ml, 4°C, 15 min) (18), and propidium iodide (PI) staining (50 µg/ml PI in 0.1% sodium citrate plus 0.1% Triton X-100; overnight incubation at 4°C) (19), as described. 7AAD and PI staining were analyzed by flow cytometry using a FACScalibur (Becton Dickinson, Mountain View, CA).

Apoptosis in response to environmental stress

For induction of apoptosis by environmental stresses, splenic T cells were activated with soluble anti-CD3{epsilon} (3 µg/ml; clone 145-2C11) plus murine rIL-2 (25 U/ml) in Iscove’s modified Dulbecco’s medium (IMDM) (10% FCS, 10-5 M ß-mercaptoethanol), as above. Activated cells were harvested using Lympholyte-M. Triplicate samples of activated splenic T cells (1 x 106) were cultured in 24-well plates (IMDM; 10% FCS, 10-5 M ß-mercaptoethanol; 2 ml final volume) and activated for 16, 24, or 48 h using the following stimuli: 1) {gamma}-irradiation (100 or 300 rad); 2) Adriamycin (0.1 or 0.2 µg/ml); 3) cisplatinum (1 or 5 µg/ml); 4) etoposide (2.5 µM); and 5) heat shock (39°C, 41°C, and 43°C for 1 h). T cells were then harvested, and triple stained with anti-CD4 (phycoerythrin), anti-CD8 (FITC), and 7AAD. Cell viability was determined by flow cytometry. Optimal time courses, concentrations, and dosage regimens for induction of cell death (LD50) were determined in pilot experiments.

Cytometry

To control for activation and to test for the expression of cell surface and activation markers, splenic T cells were stimulated as above (anti-CD3{epsilon} (3 µg/ml; clone 145-2C11) plus murine rIL-2 (25 U/ml) in IMDM medium (10% FCS, 10-5 M ß-mercaptoethanol)). Activated cells were harvested; incubated with anti-CTLA4, anti-CD69, anti-IL-2R{alpha}/CD25, anti-CD4, anti-CD8, anti-CD44, anti-ICAM-1, anti-TCR{alpha}ß, anti-CD3{epsilon}, or anti-CD95 Abs (all from PharMingen, San Diego, CA); and analyzed for the expression of cell surface markers using a FACScalibur (Becton Dickinson).

Western blotting and SAPK phosphorylation assay

Purified lymph node T cells (2 x 106) were activated with anti-CD3{epsilon} (10 µg/ml) and/or anti-CD28 (1 µg/ml), as described (17, 20, 21). Cells were lysed in ice-cold lysis buffer (10 mM NaCl, 20 mM PIPES, pH 7, 0.5% Nonidet P-40, 5 mM EDTA, 0.05 mM ß-mercaptoethanol, 100 µM Na3VO4, 50 mM NaF, 20 µg/ml leupeptin, and 1 mM benzamidine). Cleared lysates were adjusted to equal protein concentrations (Bio-Rad (Richmond, CA) protein assay). Proteins were separated by SDS-PAGE and probed for actin, Bcl-2, and Bcl-XL expression by immunoblotting using anti-actin (Sigma, St. Louis, MO), anti-Bcl-2, and anti-Bcl-XL (both from PharMingen) Abs. Activated SAPKs and SEK1 were detected using phospho-SAPK- and phospho-SEK1-specific Abs indicative of activation (New England Biolabs, Beverly, MA).


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
Enhanced TCR/CD3{epsilon} religation-induced apoptosis of Sek1-/- T cells

We have reported previously that Sek1-/-Rag-/- chimeric mice have normal numbers and ratios of CD4+ and CD8+ T cells in lymph nodes and spleen (16). However, the thymi of Sek1-/- chimeric mice were 4 to 5 times smaller than those of age-matched 129/J mice or Sek1+/+ chimeras due to a decrease in the population of double-positive thymocytes. A key result was that Sek1-/- thymocytes were more susceptible to apoptosis in response to the physiologic stimuli CD3/TCR and CD95 (16).

Religation of TCR/CD3 molecules on activated T cells leads to the induction of apoptosis in these lymphocytes (17, 22, 23). TCR/CD3 religation-mediated cell death depends on a functional TCR/CD3 signal and can be inhibited by CD28 costimulation through the induction of Bcl-XL (20, 21). To determine the role of SEK1 in TCR/CD3 religation-induced apoptosis, we activated Sek1-/- and Sek1+/+ splenic T cells with anti-CD3{epsilon} and IL-2 for 48 h. After the initial activation, the Ag receptor was religated for 48 h using an anti-CD3{epsilon}-specific mAb and IL-2. T cells from Sek1-/- chimeras were found to be significantly more susceptible to apoptosis than wild-type T cells (Fig. 1Go). Apoptosis was also enhanced in Sek1-/- T cells after TCR{alpha}ß religation using the anti-TCRß mAb H57.597 (data not shown). It should be noted that more than 95% of cells harvested from both Sek1-/- and Sek1+/+ splenic T cell cultures were activated lymphocytes that expressed TCR{alpha}ß, CD3{epsilon}, CD69, IL-2R{alpha} (CD25), CD44, ICAM-1, CTLA-4, and CD95 at comparable levels (data not shown). These results in Sek1-/- T cells indicate that SEK1 provides survival signals for mature T lymphocytes following TCR/CD3 religation.



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  		FIGURE 1. Enhanced CD3{epsilon}-mediated apoptosis in Sek1-/- T cells. A, CD3{epsilon} religation-induced apoptosis. For CD3{epsilon} religation-induced cell death, splenic T cells from one Sek1+/+ and two different Sek1-/- chimeric mice were activated for 2 days with anti-CD3{epsilon} (3 µg/ml) plus rIL-2 (25 U/ml), and subsequently religated for 48 h with plate-bound anti-CD3{epsilon}. It should be noted that exogenous rIL-2 was added to all activation and religation cultures to exclude a potential effect of IL-2 in these assays (12). Percentages of viable cells were determined in triplicate (±SD) by eosin staining of viable cells and 7AAD staining. The differences in cell viability of Sek1-/- vs Sek1+/+ T cells were statistically significant (p < 0.01; Student’s t test). Background apoptosis of nonreligated T cells was comparable among Sek1+/+ and Sek1-/- T cells (<10%). One result representative of three experiments is shown. B, PI profile for anti-CD3{epsilon} religation-induced apoptosis. The subdiploid (<G1) peak represents apoptotic cells. Different cell cycle phases (G1, S, G2/M) are indicated. Controls were T cells cultured in the absence of CD3{epsilon} religation. One result representative of three experiments is shown.

 
Since Sek1-/- chimeric mice have normal numbers of CD4+ and CD8+ T cell subpopulations in peripheral lymphatic organs and exhibit normal in vivo responses following vesicular stomatitis virus infections (12), the enhanced susceptibility of Sek1-/- T cells to TCR/CD3 religation-triggered apoptosis in vitro has no apparent role in T cell homeostasis in vivo. However, enhanced TCR/CD3-mediated apoptosis of Sek1-/- T cells might have a physiologic role following in vivo challenge with other viruses and/or bacteria.

Impaired CD3-mediated Bcl-XL up-regulation in Sek1-/- T cells

Expression of Bcl-XL is the principal mechanism that protects peripheral T cells from apoptosis (21, 24). Moreover, it has been shown that Bcl-XL, but not Bcl-2, can rescue T cells from religation-mediated cell death (20). Thus, we analyzed Bcl-XL and Bcl-2 expression in T cells following CD3{epsilon} activation (Fig. 2GoA). Interestingly, whereas CD3{epsilon} stimulation triggered Bcl-XL but not Bcl-2 expression in activated Sek1+/+ T cells, Sek1-/- T lymphocytes failed to up-regulate Bcl-XL expression.



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  		FIGURE 2. Defect in CD3{epsilon}-mediated Bcl-XL expression in Sek1-/- peripheral T cells. A, T cells were isolated from the spleens of Sek1+/+ and Sek1-/- chimeric mice and activated with anti-CD3{epsilon} (3 µg/ml) and rIL-2 (25 U/ml), as described in Figure 1Go. After 24 h of CD3{epsilon} religation (plus 50 U/ml rIL-2) (left panels) or anti-CD3{epsilon} plus CD28 religation (plus 50 U ml rIL-2) (right panels), T cells were harvested and lysed, as described in Materials and Methods. Total cell lysates were Western blotted for expression of Bcl-XL (upper panel), Bcl-2 (middle panel), and actin (lower panel). Actin is shown to control for protein levels on the gel. The proliferative responses of Sek1+/+ and Sek1-/- T cells were similar under the indicated stimulation regimen following to CD3{epsilon} cross-linking (12). Controls were T cells cultured in the absence of CD3{epsilon} religation. One result representative of three experiments is shown. B, Normal induction of SAPK/JNK in Sek1-/- T cells. Sek1+/+ and Sek1-/- lymph node T cells were not activated (control) or activated with soluble anti-CD3{epsilon} (10 µg/ml) plus soluble anti-CD28 (1 µg/ml) Abs for 5 min (37°C) (anti-CD3/CD28). Cells were lysed, and proteins were transferred on a membrane and probed for phospho-SAPK indicative of activated SAPK/JNK and total SAPK/JNK protein by Western blotting. Similar results were obtained in kinase assays using GST-c-Jun as an in vitro substrate (not shown). It should be noted that we failed to detect SAPK/JNK activation (<2 times above background) in Sek1+/+ and Sek1-/- T cells in response to CD3{epsilon} alone (not shown and Ref. 11). C, Induction of SEK1 following CD3{epsilon} stimulation. Sek1+/+ lymph node T cells were activated with soluble anti-CD3{epsilon} (10 µg/ml) Ab alone (CD3{epsilon}) or anti-CD3{epsilon} (10 µg/ml) plus soluble anti-CD28 (1 µg/ml) Abs (CD3{epsilon}/CD28) for 0, 5, and 20 min (37°C). Cells were lysed, and proteins were transferred on a membrane and probed for phospho-SEK1 indicative of activated SEK1 and total SEK1 protein (45 kDa) by Western blotting.

 
SEK1 is a direct activator of SAPKs/JNKs in response to CD28 costimulation (11, 12). Moreover, CD28 costimulation can rescue T lymphocytes from TCR/CD3{epsilon} religation-induced apoptosis via potent Bcl-XL induction (20). Interestingly, in both Sek1-/- and Sek1+/+ chimeric mice, CD28 costimulation led to comparable induction of Bcl-XL (Fig. 2GoA) and rescued T cells from TCR/CD3{epsilon} religation-induced apoptosis (Fig. 3Go). These results indicate that CD28-mediated survival signals are still operational in Sek1-/- T cells. Intriguingly, our results indicate that SEK1 links TCR/CD3 signaling, but not CD28 costimulation to the induction of Bcl-XL expression. The biochemical branch points for these differences are not known. Surprisingly, whereas CD3{epsilon} plus CD28 stimulation, but not CD3{epsilon} stimulation alone, induces activation of SAPK/JNK in Sek1-/-lymph node T cells (Fig. 2GoB), CD3{epsilon} plus CD28 stimulation and CD3{epsilon} stimulation alone can induce SEK1 activation (Fig. 2GoC).



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  		FIGURE 3. CD28-mediated survival signals are still operational in Sek1-/- T cells. Splenic T cells from Sek1+/+ and Sek1-/- chimeric mice were activated for 2 days with anti-CD3{epsilon} (3 µg/ml) plus rIL-2 (25 U/ml), and subsequently untreated for 48 h (control), religated for 48 h with plate-bound anti-CD3{epsilon} alone (CD3{epsilon}), or religated for 48 h with plate-bound anti-CD3{epsilon} plus anti-CD28 (CD3{epsilon} + CD28), as described in Materials and Methods. Viable cells were determined in triplicate (±SD) by eosin and 7AAD staining, and percentages of viable cells were calculated relative to control values (100%). Background apoptosis of control nonreligated T cells was comparable among Sek1+/+ and Sek1-/- T cells (<10%). Note enhanced apoptosis of Sek1-/- T cells following CD3{epsilon} religation alone. Differences in cell viability of CD3{epsilon}-religated Sek1-/- vs Sek1+/+ T cells were statistically significant (p < 0.01; Student’s t test). One result representative of three experiments is shown.

 
Since TCR/CD3 activation of Sek1+/+ T cells leads to SEK1 activation, but TCR/CD3 activation of Sek1+/+ and Sek1-/-thymocytes and peripheral T cells does not induce SAPK/JNK activity (data not shown and 11 , these results suggest that SEK1-mediated survival signals might be independent of SAPK/JNK activation. Thus, SEK1 might function in a novel and distinct signaling pathway. Alternatively, we cannot exclude the possibility that the Sek1 mutation effects thymocyte maturation and that the population of peripheral T cells in these chimeric mice may be biologically different from peripheral T cells in normal mice. In addition to impaired Bcl-XL expression, alternate possibilities, including down-regulation of Bax or Bad, failure to activate Nur77, underexpression of caspases, or overexpression of IAPs, might account for impaired apoptosis in SEK1/MKK4-deficient T cells. Nevertheless, our results clearly indicate that SEK1 expression is important for Bcl-XL expression and to provide survival signals in CD3-activated peripheral T cells.

T cell death in response to metabolic poisons

It has been proposed from transfection studies with dominant negative signaling mutants that the SEK1->SAPK/JNK signaling cascade may be a common intracellular pathway required for the induction of apoptosis in response to many types of cellular stresses (7, 8, 9, 10). However, we could not observe any significant differences between freshly isolated (not shown) or activated (rIL-2 and anti-CD3{epsilon}) Sek1-/- and Sek1+/+ peripheral T cells in either the extent or kinetics of cell death in response to cisplatinum, Adriamycin, {gamma}-irradiation, etoposide (Fig. 4Go), heat shock, or UV irradiation (not shown). It should be noted that heat shock and UV irradiation do not induce SAPK/JNK activity in Sek1-/- cells, whereas all other indicated poisons can still activate SAPK/JNK presumably via activation of SEK2/MKK7 (16, 25, 26). Thus, our results do not support the hypothesis that SEK1-mediated activation of SAPKs/JNKs is required for the induction of T cell death in response to UV irradiation and heat shock. These results imply that enhanced TCR/CD3-mediated apoptosis of Sek1-/- T cells is not due to increased susceptibility to cell death per se, but appears to be specific for TCR/CD3-triggered death signals. SEK1-independent signaling cascades are operative during the induction of apoptosis in response to metabolic poisons.



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  		FIGURE 4. Induction of T cell apoptosis by cisplatinum, Adriamycin, {gamma}-irradiation, and etoposide. Splenic T cells were activated with anti-CD3{epsilon} (3 µg/ml) and rIL-2 (25 U/ml), and subsequently stimulated for 24 h with environmental poisons. The various compound concentrations and dosages of {gamma}-irradiation are indicated. Cell viability was determined in triplicate by 7AAD and PI staining and compared with the viability of cells cultured in the absence of the indicated poisons (percentage of viable cells). One result of a triplicate culture (±SD) representative of five independent experiments is shown for each activation.

 
Conclusion

We report in Sek1-/-RAG-/- chimeric mice that a null mutation of the dual specificity stress kinase SEK1/MKK4 facilitates TCR/CD3{epsilon} religation-induced cell death of activated peripheral T cells. Sek1-/- T cells failed to up-regulate the death suppressor Bcl-XL following CD3{epsilon} activation. However, CD28 costimulation induced normal Bcl-XL expression in Sek1-/- T cells and rescued activated Sek1-/- T cells from TCR/CD3{epsilon} religation-mediated apoptosis. Sek1-/- T cells displayed normal susceptibility to apoptosis in response to various environmental stresses. We also report that TCR/CD3 activation alone induces SEK1 phosphorylation. Our data in Sek1 gene-targeted T cells indicate that SEK1 mediates survival signals required by T cells to resist premature apoptosis during activation. These results provide a mechanistic explanation for enhanced cell death of Sek1-/- T lymphocytes in response to TCR/CD3{epsilon} religation.


   Acknowledgments
 
We thank R. Miller, K. D. Fischer, K. Bachmaier, J. Woodgett, A. Hakem, Y. Y. Kong, and A. J. Oliveira-dos-Santos for comments.


   Footnotes
 
1 Address correspondence and reprint requests to Dr. Josef M. Penninger, Amgen Institute, and Ontario Cancer Institute, Departments of Medical Biophysics and Immunology, University of Toronto, 620 University Avenue, Suite 706, Toronto, Ontario M5G 2C1. E-mail address: Back

2 Abbreviations used in this paper: SAPK, stress-activated protein kinase; 7AAD, 7- aminoactinomycin D; IMDM, Iscove’s modified Dulbecco’s medium; JNK, c-Jun NH2-terminal kinase; MKK, mitogen-activated protein kinase-kinase; PI, propidium iodide; SEK, stress-activated protein kinase/extracellular signal-regulated kinase kinase. Back

Received for publication November 12, 1997. Accepted for publication June 3, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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