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The Journal of Immunology, 1999, 162: 1896-1903.
Copyright © 1999 by The American Association of Immunologists

Differential Effects of IL-2 and IL-15 on the Death and Survival of Activated TCR{gamma}{delta}+ Intestinal Intraepithelial Lymphocytes1

Ching-Liang Chu*,{dagger}, Shih-Shun Chen*,{dagger}, Tzong-Shoon Wu{dagger}, Szu-Cheng Kuo{dagger} and Nan-Shih Liao2,*,{dagger}

* Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan; and {dagger} Institute of Molecular Biology, Academia Sinica, Nankang, Taipei, Taiwan


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
TCR{gamma}{delta}+ cells are enriched in the intestine mucosa and constitute approximately half of the intestinal intraepithelial lymphocytes (iIEL) in mice. They are likely activated by self and foreign Ags in situ, but little is known about how the activated {gamma}{delta} iIEL are regulated. In the iIEL compartment, IL-2 is produced by activated TCR{alpha}ß+ iIEL, and IL-15 message is detected in iIEL and in the epithelial cells. We found surface expression of IL-2 as well as IL-15Rs on activated {gamma}{delta} iIEL, and examined the effects of IL-2 and IL-15 on the survival and death of {gamma}{delta} iIEL during secondary stimulation through TCR. We found that both cytokines supported growth of the restimulated {gamma}{delta} iIEL, but exerted different effects on their survival. A significant higher number of live cells were recovered from the {gamma}{delta} iIEL cultures restimulated in IL-15 than in IL-2. Quantitation of apoptotic cells showed more cell death in the IL-2 group than in the IL-15 group. The cell death was associated with restimulation through TCR and was not caused by insufficient growth factor, thus representing activation-induced cell death. Western blot analyses found no difference in the levels of Bcl-2 and Bax proteins between the two groups. However, the level of Bcl-xL protein diminished with time in the IL-2 group whereas the level was sustained in the IL-15 group, which may contribute to the pro-survival effect of IL-15. These results demonstrated that the survival of activated {gamma}{delta} iIEL is differentially regulated by IL-2 and IL-15.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Intestinal intraepithelial lymphocytes (iIEL)3 are T cells that reside in between the epithelial cells that line the intestine lumen. These T cells are phenotypically and functionally distinct from T cells of the central immune system 1 . Approximately half of the iIEL express TCR{gamma}{delta} ({gamma}{delta} iIEL). Among them, most are CD8{alpha}{alpha}+ cells with the rest being CD4-CD8-, a phenotype that resembles {gamma}{delta} T cells in the central immune system 2, 3, 4 . Other unique features of {gamma}{delta} iIEL include their extrathymic origin 5 and usage of the Fc{epsilon}R {gamma}-chain in the TCR signaling module 6, 7, 8 . {gamma}{delta} iIEL are actively involved in the normal biology of the intestine mucosa. They have been shown to proliferate, produce cytokines, and exert cytotoxicity in response to TCR stimulation or infection 4, 9, 10 . Studies using mice deficient in TCR{gamma}{delta} suggest the involvement of {gamma}{delta} iIEL in turnover of the intestinal epithelial cells (IEC) 11 , in generation of IgA response to Ags delivered orally 12 , and in down-regulation of {alpha}ß T cell-mediated immune responses in the intestine 13 . Many of these activities were observed when cells or animals were stimulated with either TCR-specific Abs or Ags/pathogens. However, little is known about the regulation of {gamma}{delta} iIEL along the course of their activation.

IL-15 is a recently identified T cell growth factor that shares some activities with IL-2 14 . Despite the lack of significant sequence homology to IL-2, IL-15 binds to IL-2R ß- and {gamma}-chains and results in signal transduction 15, 16 . A novel IL-15R {alpha}-chain was also identified 17 . In contrast to the T cell-restricted expression of IL-2, IL-15 mRNA is detected in various tissues and cell types 14 , including primary IEC and iIEL (Refs. 18 and 19 and our unpublished observations). The IL-15 protein was also detected in human (h) IEC lines by Western blot analysis 19 . Because IL-15 supports proliferation of epidermal and intestinal {gamma}{delta} IEL in vitro 18, 20 , it is likely used as a local cytokine by {gamma}{delta} iIEL.

Activated T cells undergo apoptosis upon repeated stimulation. This activation-induced cell death (AICD) is an important mechanism underlying peripheral tolerance 21 and may also contribute to T cell homeostasis after an immune response 22 . In addition to repeated stimulation through TCR, the prototype T cell growth factor, IL-2, was also shown to promote AICD at the late stage of T cell activation 23, 24, 25 . Although most studies on AICD of normal T cells were performed on TCR{alpha}ß+ T cells, especially the CD4+ subset, little is known about AICD of TCR{gamma}{delta}+ cells. In this study, we compared the effects between IL-15 and IL-2 on the survival and death of {gamma}{delta} iIEL receiving secondary stimulation through TCR.


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

C57BL/6 mice were purchased from Cheng-Kung University (Tainan, Taiwan) and bred at the animal facility at the Institute of Molecular Biology, Academia Sinica (Nankang, Taipei) under specific pathogen-free conditions. Ten- to 14-wk-old males were starved overnight before being used for experiments.

Antibodies

Abs used include anti-TCR{gamma}{delta} FITC (clone GL3) 26 , anti-TCR{alpha}ß FITC (clone H57-597) 27 , anti-CD8{alpha} PE (clone 53-6.7; Caltag Laboratories, San Francisco, CA), anti-CD25 PE (clone 7D4; Caltag Laboratories), anti-CD122 FITC (clone 5H4; PharMingen, San Diego, CA), anti-CD132 biotin (clone 4G3; PharMingen), anti-IL-2 neutralizing mAb (clone S4B6; 28 , goat-anti-mouse IL-15R{alpha} Ab (Santa Cruz Biotechnology, Santa Cruz, CA), and donkey-anti-goat IgG FITC (Jackson ImmunoResearch Laboratories, West Grove, PA). Monoclonal Ab specific for Bcl-2, Bcl-x, and Bax were purchased from Santa Cruz Biotechnology.

Primary activation of {gamma}{delta} iIEL

Total iIEL were isolated as described 29 with some modifications. Briefly, iIEL were dissociated from small intestine pieces in Ca2+-, Mg2+-free PBS (Life Technologies, Grand Island, NY) containing 1 mM DTT and 1 mM EDTA by stirring at 37°C for 40 min, and then enriched by filtration through nylon wool columns and by centrifugation in a discontinuous Percoll gradient (40%/70%). Total iIEL were panned on tissue culture dishes (100 mm diameter) precoated with GL3 mAb (10 µg) for 1 h. After removal of the nonadherent cells, the adherent cells were cultured in RPMI 1640 (Life Technologies) supplemented with 2 mM L-glutamine, 20 mM HEPES, 2000 U/liter penicillin/streptomycin, 5 x 10-5 M 2-ME, 10% FCS, and 10 ng/ml mouse (m) rIL-2 (R&D Systems, Minneapolis, MN) for 7 days. Activated {gamma}{delta} iIEL were then transferred to new dishes without GL3 coating to rest for 1 day before restimulation.

Restimulation of activated {gamma}{delta} iIEL

Cells harvested from the rested primary culture were centrifuged through Ficoll (density, 1.09) to remove dead cells. Live cells (2 x 104 cells/well) were restimulated in 96-well half-area tissue culture plates (Corning, Corning, NY) precoated with GL3 (0.2 µg/well) in 200 µl of RPMI/10% FCS containing rmIL-2, rhIL-15 (R&D Systems), or both cytokines at indicated concentrations for indicated periods of time. Each well was replaced with 50 µl of fresh medium and cytokine(s) every 2 days.

Measurement of cell growth

Cell proliferation was determined by [3H]TdR incorporation in which 1 µCi/well of [3H]TdR (Amersham, Buckinghamshire, U.K.) was added to each well 12 h before harvesting or by counting the number of live cells defined by trypan blue exclusion under microscope.

Measurement of cell death

Apoptosis was determined by two methods. One was to stain suspension cells with propidium iodide (PI) and then analyze by FACScan (Becton Dickinson, Mountain View, CA) as previously described 30 . Cells with subdiploid DNA content were taken as apoptotic cells. Another method was to assess nuclear morphology. Parafomaldehyde-fixed cells were air dried onto slides and then stained with PI in PBS containing 0.3% Triton X-100. The cells were then observed using a laser scanning confocal microscope (LSM 310; Zeiss, Oberkochen, Germany).

Western blot analysis

Restimulated {gamma}{delta} iIEL were harvested at indicated time points. After removal of dead cells by centrifugation through Ficoll, cells were lysed in lysis buffer containing 20 mM Tris-HCl (pH 7.6), 0.15 M NaCl, 2 mM EDTA, 1% Triton X-100, 50 mM NaF, 0.1 mM Na3VO4, and 0.3 mM PMSF for 30 min on ice. Fifty micrograms of protein from each sample were boiled in sample buffer for 5 min and analyzed by 12% SDS-PAGE. Proteins were transferred from gel to polyvinylidene difluoride membranes (Millipore, Bedford, MA) that were then blocked with 5% skim milk in PBS and reacted with various Abs. The binding of Ab was detected by using the horseradish peroxidase-conjugated goat anti-rabbit IgG (Caltag Laboratories). The blots were detected using enhanced chemiluminescence (Amersham).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Activated {gamma}{delta} iIEL expressed all components of IL-2R and IL-15R

Freshly isolated iIEL that adhered to anti-TCR{gamma}{delta} mAb-coated plates were cultured in IL-2 for 7 days and then examined for expression of surface markers by staining with specific Abs. Flow cytometry analyses showed that all cells were TCR{gamma}{delta}+ with most expressing CD8{alpha} (Fig. 1Go, A–C). They also expressed all components of the IL-2R (Fig. 1Go, D–F). To determine whether IL-15R {alpha}-chain is expressed on the surface of activated {gamma}{delta} iIEL, cells were stained with a polyclonal Ab and observed under confocal microscope (Fig. 2Go). As shown in Fig. 2GoC, a weak but clear surface staining was demonstrated. These results suggest that the activated {gamma}{delta} iIEL could be affected by IL-2 and IL-15 upon restimulation.



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  		FIGURE 1. Surface marker expression by activated {gamma}{delta} iIEL. Freshly isolated iIEL that adhered to GL3 mAb-coated plates were cultured in medium supplemented with 10 ng/ml of mrIL-2 for 7 days and then analyzed for expression of TCR{gamma}{delta} (A), TCR{alpha}ß (B), CD8{alpha} (C), and the components of IL-2R including CD25 (D), CD122 (E), and CD132 (F) by staining with the specific mAb and analyzing with flow cytometry. The grey line represents the background fluorescence of unstained cells. Similar results were obtained from three independent experiments.

 


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  		FIGURE 2. Activated {gamma}{delta} iIEL showed surface expression of IL-15R {alpha}-chain. Activated {gamma}{delta} iIEL as described in Fig. 1Go were stained with donkey anti-goat IgG FITC alone (A), or with goat-anti-mIL-15R{alpha} Ab and followed with donkey-anti-goat IgG FITC (C). The cells were then mounted onto slides and observed with the confocal microscope. The bright field images of A and C are displayed in B and D, respectively, to reveal the location of the cells. The arrows in C and D point to the same cells. Similar results were obtained from three independent experiments.

 
IL-2 and IL-15 supported the growth of restimulated {gamma}{delta} iIEL

We then determined the optimal concentrations of IL-2 and IL-15 to use in restimulation of {gamma}{delta} iIEL. As shown in Fig. 3Go, exogenous IL-2 or IL-15 supported proliferation of the restimulated {gamma}{delta} iIEL in a dose-dependent manner in which a plateau was reached at 20 ng/ml of IL-2 or 200 ng/ml of IL-15. These concentrations were used in all later experiments unless otherwise specified. It is worth noting that without exogenous cytokine, the restimulated {gamma}{delta} iIEL did not proliferate, but underwent apoptosis even in the presence of CD28 costimulation (data not shown), suggesting that {gamma}{delta} iIEL produced little growth factor(s) under the given activation condition. To determine whether the growth-supporting effect of IL-15 was mediated through induction of IL-2, IL-2-specific neutralizing mAb was used. As shown in Fig. 4Go, although 50 µg/ml of neutralizing mAb completely blocked the proliferation of {gamma}{delta} iIEL restimulated in the presence of exogenous IL-2 and caused cell death, it had little effect on the proliferation and survival of cells restimulated in the presence of exogenous IL-15. The amount of IL-2 in the supernatant of the IL-15 culture was below the detection sensitivity of ELISA (data not shown). These results indicate that the growth promoting effect of IL-15 on restimulated {gamma}{delta} iIEL is independent of IL-2.



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  		FIGURE 3. IL-2 and IL-15 supported the growth of restimulated {gamma}{delta} iIEL. Activated {gamma}{delta} iIEL were restimulated through TCR as described in Materials and Methods in medium alone or plus various amounts of mrIL-2 (A) or hrIL-15 (B) for 2 days. Cell proliferation and apoptosis were determined by measurement of [3H]TdR incorporation and by staining permeated cells with PI, respectively, as described in Materials and Methods. The percent apoptosis represents the percentage of cells with subdiploid DNA content. All data points were the average of triplicate samples, and the error bars represent the sample SD. Similar results were obtained from three independent experiments.

 


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  		FIGURE 4. IL-15 promoted cell growth independent of IL-2. Activated {gamma}{delta} iIEL were restimulated through TCR as described in Materials and Methods in the presence of 20 ng/ml of IL-2 or 200 ng/ml of IL-15 with or without 50 µg/ml of IL-2-specific neutralizing mAb for 2 days. Cell proliferation and apoptosis were determined as described in the legend of Fig. 3Go. All data points were the average of triplicate samples and the error bars represent the sample SD. Similar results were obtained from two independent experiments.

 
Differential effects of IL-15 and IL-2 on the restimulated {gamma}{delta} iIEL

To examine the effects of IL-2 vs IL-15 on restimulation of {gamma}{delta} iIEL, we followed the growth kinetics of restimulated {gamma}{delta} iIEL up to 8 days and found significantly higher numbers of live cells and [3H]TdR incorporation in the IL-15 group than in the IL-2 group starting from day 4 (Fig. 5Go, A and B). As the difference in viable cell counts was more distinct than in [3H]TdR incorporation between the two groups, mechanisms other than proliferation might contribute to the difference in the live cells numbers. We then examined cell death along the course of restimulation by quantitating cells with subdiploid DNA content using flow cytometry (Fig. 5GoC). We found that the percentage of dead cells was significantly higher in the IL-2 group than in the IL-15 group. On the other hand, cells cultured in IL-2 or in IL-15 without restimulation through TCR showed only low levels of apoptosis (Fig. 5GoC). Therefore, the observed cell death was induced by activation through TCR, which agrees with the definition of AICD. We also examined the nuclear morphology of the {gamma}{delta} iIEL before and after restimulation (Fig. 5GoD and Table IGo). After primary activation for 7 days, most cells showed healthy nuclear morphology with ~6% of the cells displaying apoptosis features. After restimulation through TCR, the percentages of apoptotic cells in the IL-2 group were significantly higher than those in the IL-15 group at various time points. This method detected earlier and higher numbers of apoptotic events than measurement of subdiploid DNA content in cells, probably because nuclear morphology reveals the earlier apoptosis feature, i.e., DNA condensation, as well as the later DNA fragmentation and formation of apoptotic bodies. Both methods demonstrated higher cell death in the IL-2 group than in the IL-15 group. These results suggest that IL-15 is more efficient than IL-2 in supporting the growth of restimulated {gamma}{delta} iIEL via protecting cells from AICD.



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  		FIGURE 5. Differential effects of IL-2 and IL-15 on the restimulated {gamma}{delta} iIEL. Activated {gamma}{delta} iIEL were restimulated through TCR as described in Materials and Methods in the presence of 20 ng/ml of IL-2 (solid square) or 200 ng/ml of IL-15 (solid triangle) for 8 days. A, The viable cell count was determined by trypan blue exclusion. B, Cell proliferation was determined by [3H]TdR incorporation. C, Cell death was determined by PI staining and flow cytometry analyses. Cells that did not receive restimulation through TCR were included in C (open symbols). All data points were the average of triplicate samples and the error bars represent the sample SD. Apoptosis was also assessed by nuclear morphology as described in Materials and Methods (Table IGo). Cells restimulated for 4 days in IL-2 (D) or in IL-15 (D') are shown here. Arrows indicate cells with normal nuclear morphology and arrowheads indicate cells showing DNA condensation or apoptotic bodies. Similar results were obtained from three independent experiments.

 

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  		Table I. Apoptosis of {gamma}{delta} iIEL restimulated in IL-2 or IL-151

 
The death of {gamma}{delta} iIEL restimulated in IL-2 was not due to insufficient cytokine

Because IL-2 is also used as a growth factor by the restimulated {gamma}{delta} iIEL, cell death may result from insufficient amounts of cytokine present during later periods of culturing even though {gamma}{delta} iIEL were fed with fresh medium containing IL-2 every 2 days. To test this possibility, the growth and death kinetics of {gamma}{delta} iIEL restimulated at various concentrations of IL-2 were examined (Fig. 6Go). Cells activated in 5 ng/ml of exogenous IL-2, a suboptimal concentration (Fig. 3GoA), showed the lowest viable cell counts and the highest level of apoptosis, reflecting an insufficient presence of growth factor. When 50 and 100 ng/ml of IL-2 were used, which represented 2.5- and 5-fold of the optimal concentration, respectively, the numbers of viable cells and the percentage of apoptotic cells were similar to those of cells activated in 20 ng/ml of IL-2. These results indicate that the death of {gamma}{delta} iIEL restimulated in 20 ng/ml of IL-2 was not due to insufficient cytokine.



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  		FIGURE 6. Cell death in the IL-2 group was not caused by insufficient growth factor. Activated {gamma}{delta} iIEL collected from primary culture were restimulated through TCR as described in Materials and Methods in 5 ng/ml (diamond), 20 ng/ml (solid square), 50 ng/ml (circle), and 100 ng/ml (inverted triangle) of IL-2 for 8 days. The viable cell counts were determined by trypan blue exclusion. Cell death was determined by PI staining and flow cytometry analyses. All data points were the average of triplicate samples and the error bars represent the sample SD. Similar results were obtained from two independent experiments.

 
The pro-apoptosis effect of IL-2 was dominant over the anti-apoptosis effect of IL-15

Because IL-2 and IL-15 both bind to the IL-2R ß- and {gamma}-chains but exert different effects on restimulated {gamma}{delta} iIEL, we examined the growth and death kinetics of {gamma}{delta} iIEL restimulated in the presence of both cytokines (Fig. 7Go). Addition of 5 ng/ml of IL-2 into the IL-15 culture resulted in a significant drop of viable cell numbers and an increment of cell death. Addition of 20 or 50 ng/ml of IL-2 further decreased the number of live cells to a level similar to that exhibited when 20 ng/ml of IL-2 alone was used. These results showed that the pro-apoptotic effect of IL-2 was dominant over the anti-apoptotic effect of IL-15 on restimulated {gamma}{delta} iIEL under the given conditions. The addition of IL-2 into the IL-15 culture promoted death rather than life of the restimulated cells further ruling out the possibility that death was caused by insufficient growth factor.



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  		FIGURE 7. IL-2 promoted AICD of restimulated {gamma}{delta} iIEL in the presence of IL-15. Activated {gamma}{delta} iIEL collected from primary culture were restimulated through TCR as described in Materials and Methods in the presence of 20 ng/ml of IL-2 (solid square), 200 ng/ml of IL-15 (solid triangle), or IL-15 plus 5 ng/ml (diamond), 20 ng/ml (square), or 50 ng/ml (circle) of IL-2 for 8 days. The viable cell counts and cell death were determined as described in the legend of Fig. 6Go. All data points were the average of triplicate samples, and the error bars represent the sample SD. Similar results were obtained from two independent experiments.

 
The level of Bcl-xL was maintained in {gamma}{delta} iIEL restimulated in IL-15

As the members of the Bcl gene family are critical in determination of the life and death of T cells 31 , we analyzed the amounts of two survival-promoting members, Bcl-2 and Bcl-xL, and a death-promoting member, Bax, in {gamma}{delta} iIEL at various time points during restimulation in IL-2 or in IL-15 by Western blot analysis. As shown in Fig. 8Go, the level of Bcl-2 and Bax proteins did not change along the course of restimulation in either the IL-2 or the IL-15 group and was quite similar in both groups. In the case of Bcl-xL, the protein level between the IL-2 and IL-15 groups was similar at 2, 4, and 5 days after restimulation. This level was maintained in the IL-15 group, but reduced in the IL-2 group, starting ~6 days after restimulation, when significant difference in viable cell numbers between the two groups was observed (Fig. 5GoA). These results demonstrate a correlation between cell death and the reduction of Bcl-xL in the {gamma}{delta} iIEL restimulated in IL-2, which suggests that IL-15 protects {gamma}{delta} iIEL from AICD by sustaining the expression of Bcl-xL or that IL-2 promotes AICD by down-regulating the expression of Bcl-xL.



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  		FIGURE 8. Expression of Bcl-xL, Bcl-2, and Bax by {gamma}{delta} iIEL restimulated in IL-2 or in IL-15. Activated {gamma}{delta} iIEL collected from primary culture were restimulated through TCR as described in Materials and Methods in 20 ng/ml of IL-2 or in 200 ng/ml of IL-15 for 8 days. Viable cells were harvested at indicated time points and analyzed for expression of Bcl-xL, Bcl-2, and Bax by Western blotting as described in Materials and Methods. Similar results were obtained from two independent experiments.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Activation of {gamma}{delta} iIEL through TCR by foreign and self Ags is likely to constantly occur in the intestine mucosa 32, 33, 34 . In the iIEL compartment, IL-2 is produced by activated CD4+, CD4+CD8+, and CD8{alpha}ß+ TCR{alpha}ß+ cells 35, 36 , and the IL-15 mRNA was detected in both {alpha}ß and {gamma}{delta} iIEL and in IEC. In the present study, we demonstrated surface expression of all the components of the IL-15R and IL-2R on activated {gamma}{delta} iIEL. We also demonstrated AICD of {gamma}{delta} iIEL that received secondary stimulation through TCR and examined the role of IL-2 and IL-15 in the survival and death of the restimulated {gamma}{delta} iIEL. We found that exogenous IL-2 or IL-15 supported the growth of the restimulated {gamma}{delta} iIEL that would otherwise not have proliferated but would have die. However, only minimal increment in viable cell numbers was observed in the IL-2 group in comparison with the significant increase in the IL-15 group along the course of restimulation. Quantitation of apoptotic cells revealed higher AICD in the IL-2 group than in the IL-15 group, indicating a protective role of IL-15 in AICD of {gamma}{delta} iIEL. Similar protective effect of IL-15 on TCR-triggered apoptosis was observed in CD8{alpha}{alpha}+ {alpha}ß iIEL, but not in CD8{alpha}ß+ {alpha}ß iIEL, during primary activation (our unpublished data), which suggests that the rescue by IL-15 is not specific for {gamma}{delta} T cells in the gut but may be specific for cells of CD8{alpha}{alpha}+ phenotype. We are currently examining the effect of IL-15 on AICD of peripheral {gamma}{delta} T cells which are mainly comprised of CD4-CD8-. The pro-survival effect of IL-15 observed in this study is consistent with previous observations in activated human peripheral blood B and T cells in which IL-15 promoted their survival upon cross-linking of Fas or antigenic receptors 37 . IL-15 was also shown to protect the activation-independent passive cell death 21 of freshly isolated hNK cells 38 and neutrophils 39 , as well as murine {gamma}{delta} iIEL 18 .

IL-2 is the prototype T cell survival and growth factor. Interestingly, IL-2 gene knockout mice show accumulation of superantigen-stimulated peripheral T cells and B220+TCRlow intrahepatic T cells 25, 40 , indicating that IL-2 is required for the elimination of activated T cells in vivo. The involvement of IL-2 in AICD of CD4+ T cells via the Fas/Fas ligand pathway was also demonstrated 23, 24 . In the case of {gamma}{delta} T cells, an earlier study showed that anti-TCR mAb induced apoptosis of hCD4-CD8- {gamma}{delta} T cell clones in the presence of IL-2 41 . Recently, IL-2 was shown to enhance apoptosis of Mycobacterium tuberculosis-reactive human V{gamma}9+/V{delta}2+ cells upon restimulation with Ags 42 . However, the role of IL-2 in AICD of {gamma}{delta} iIEL has not been elucidated. In this study, we found that IL-2 supported cell proliferation but also promoted AICD of {gamma}{delta} iIEL during secondary stimulation through TCR.

When IL-2 was titrated into the IL-15 culture of restimulated {gamma}{delta} iIEL, the pro-apoptotic effect of IL-2 dominated the pro-survival effect of IL-15 (Fig. 6Go). A possible reason is that the pro-apoptotic signals, triggered by IL-2, dominate the pro-survival signals triggered by IL-15. However, it was unexpected that 5 ng/ml (0.29 µM) of IL-2 rendered a significant drop of viable cell numbers in {gamma}{delta} iIEL restimulated in 200 ng/ml (16 µM) of IL-15. The much greater effectiveness of IL-2 than IL-15 raises the possibility that hIL-15 binds less efficiently than mIL-2 to mIL-2R. This possibility is supported by the observation that simian IL-15, with 95% homology to hIL-15 43 , can bind and signal through hIL-2R ß{gamma}-chains 44 but not mIL-2R ß{gamma}-chains unless in the presence of mIL-15R {alpha}-chain 17 . Furthermore, in screening of a panel of murine and human hematopoietic cells, the affinity of simian IL-15 was on average higher for the human cells than for the murine cells 15 . On the other hand, it has been clearly demonstrated that simian IL-15 binds to mIL-15R{alpha}ß{gamma} with high affinity 17 . Another possibility is that the IL-15/ß{gamma} ligand/receptor complex is less stable than the IL-2/ß{gamma} complex as demonstrated in a study using simian IL-15 and hIL-2 on human cells 45 . In the same study, it was shown that 32-fold more of IL-15 was needed to reach the same level of proliferation of peripheral blood T blasts stimulated by IL-2, which is closed to the 53-fold difference between IL-15 (16 µM) and IL-2 (0.29 µM) observed in Fig. 6Go of this study. Therefore, the difference between the stability of the two ligand/receptor complexes may result in qualitative difference in signaling. However, to conclude that the pro-apoptotic signals delivered by IL-2 indeed dominate the pro-survival signals delivered by IL-15 requires the elucidation of their signaling pathways.

One unique feature of the AICD of the {gamma}{delta} iIEL in this study is its much delayed kinetics compared with the kinetics of CD4+ T cells restimulated by superantigen 46 . The slower kinetics in acquiring sensitivity to AICD in normal human blood CD4-CD8- {gamma}{delta} T cell clones than in {alpha}ß T cells was previously reported 47 . Although the cause of the delayed AICD phenotype is not known, it may reflect an intrinsic property of {gamma}{delta} iIEL, as suggested by the higher resistance to irradiation- or glucocorticoids-induced death and the higher expression of Bcl-2 and Bcl-xL in freshly isolated iIEL than in peripheral lymph node cells 48 .

Bcl-2 and Bcl-xL promote cell survival by inhibition of mitochondrial permeability transition, a common downstream event shared by apoptosis triggered by various initial stimuli 49, 50, 51 . Although both molecules block T cell apoptosis, they are likely to operate under different conditions. Bcl-2 inhibits passive cell death and death caused by {gamma}-irradiation and glucocorticoids 21, 52 , but not AICD via the Fas pathway 53, 54 . Augmentation of Bcl-xL expression by CD28 costimulation correlates with the enhanced T cell survival during primary activation 55, 56 ; however, the role of Bcl-xL in AICD is less clear. Transfection of Bcl-xL was shown to block Fas-mediated and to a lesser extent CD3-mediated apoptosis of Jurkat cells 49, 55 , but had no effect on AICD of the murine T cell hybridoma 2B4 triggered by anti-CD3 mAb 57 . In this study, {gamma}{delta} iIEL restimulated in either IL-2 or IL-15 expressed the same level of Bcl-2 during the 8-day restimulation period. This is consistent with the notions that Bcl-2 does not block AICD of peripheral T cells, and that Bcl-2 expression is induced by signaling through the IL-2R ß-chain 58 . On the other hand, the level of Bcl-xL diminished with time in the IL-2 group, but was maintained in the IL-15 group. This result suggest that Bcl-xL may contribute to the protective role of IL-15 in AICD of murine {gamma}{delta} iIEL.

The distinct effect of IL-2 and IL-15 on AICD of {gamma}{delta} iIEL suggests that the survival of activated {gamma}{delta} iIEL is well regulated. The presence of IL-15 in the microenvironment, e.g., through production by IEC, would allow the activated {gamma}{delta} iIEL to live and to carry out their function. When IL-2 comes into the picture, e.g., through production by activated {alpha}ß iIEL, activated {gamma}{delta} iIEL would die by AICD. The dynamic interactions among the stimuli that modulate cytokine production, the cytokine producers, and the iIEL as the effectors could ultimately determine the fate of the activated {gamma}{delta} iIEL. This possibility may provide a basis for further studies into the regulation of iIEL function and mucosal immunity.


   Acknowledgments
 
We thank Dr. S. T. Ju (Boston University School of Medicine, Boston, MA) for constructive discussion of the experiments.


   Footnotes
 
1 This work was supported by Grant 86-5202401224-4 from Academia Sinica and Grant NSC 88-2311-B001-119 from the National Science Council, Taiwan. Back

2 Address correspondence and reprint requests to Dr. Nan-Shih Liao, Institute of Molecular Biology, Academia Sinica, Nankang, Taipei 11529, Taiwan. E-mail address: Back

3 Abbreviations used in this paper: iIEL, intestinal intraepithelial lymphocytes; IEC, intestinal epithelial cells; AICD, activation-induced cell death; PI, propidium iodide; h, human; m, mouse. Back

Received for publication September 9, 1998. Accepted for publication November 6, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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