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The Journal of Immunology, 2003, 171: 1128-1132.
Copyright © 2003 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: T Lymphocyte Activation by Repeated Immunological Synapse Formation and Intermittent Signaling 1

Mustapha Faroudi, Rossana Zaru, Pierre Paulet, Sabina Müller and Salvatore Valitutti2

Institut National de la Santé et de la Recherche Médicale Unité 563, Lymphocyte Interaction Group, Institut Claude de Préval, Toulouse, France


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
The activation of biological T cell responses requires prolonged contact with APCs and sustained signaling. We investigated whether signaling must be uninterrupted to commit T cells to cytokine production or whether T cell activation may also result from summation of interrupted signals. Upon periodic addition and removal of a src kinase inhibitor, human CD4+ T cells destroyed and re-formed immunological synapses while aborting and restarting signal transduction. Remarkably, under these conditions, T cells were eventually activated to IFN-{gamma} production and the amount of IFN-{gamma} produced was directly related to the total signaling time despite the repeated interruptions. Our results illustrate that T cell activation does not require a stable immunological synapse and can be achieved by interrupted signaling. It is implied that T cells can add activation signals, possibly collected on multiple APCs.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
An unresolved question in T lymphocyte activation concerns the nature of the interaction between T cells and APCs. It is well established that T cells need to undergo sustained signaling to be committed to IL production (1). However, it is still unclear whether sustained signaling requires a prolonged interaction with the same APC or whether it can be generated by sequential multiple encounters with different APCs (2). Although the capacity of CTLs to recycle from one target to another with an eventual activation has been thoroughly documented (3), this phenomenon has never been observed for CD4+ T cells interacting with APCs during long lasting in vitro cultures. Th cells are known to form stable clusters with cognate APCs (4), suggesting that they may be rather "monogamous" cells.

A characteristic of T cell Ag recognition that does not fit well with the notion of "monogamous" Th cells concerns the high degree of mobility of the T cell-APC interaction. T cells exhibit a spontaneous, actin cytoskeleton-dependent mobility that allows them to migrate both in vitro and in vivo (5). Although upon conjugation with cognate APCs T cells undergo a change of shape and stop their progression, this "stop signal" is often transient (5, 6). Within a few minutes after conjugate formation, T cells can start to move again and crawl on the APC surface while undergoing sustained signaling (5).

A recent study showed that interactions of CD4+ T cells with dendritic cells in a collagen matrix (but not in liquid culture media) are short lived and sequential (7). This indicates that a three-dimensional environment may favor T cell locomotion and sequential APC encounter. This study documents for the first time that CD4+ T cells can be activated in the absence of stable APC contacts. However, the question whether individual T cells can add up interrupted signals and exhibit biological responses corresponding to the accumulated signal has not been addressed.

To address this question, we studied immunological synapse (IS)3 formation, TCR-mediated signal transduction and IFN-{gamma} production in T cells conjugated with APCs in which the signal transduction was periodically blocked by the sequential addition and removal of the src kinase inhibitor PP2. This inhibitor has indeed been reported to block both TCR- and integrin-mediated signal transduction in T cells (8, 9). We report that individual T lymphocytes can rapidly re-form a destroyed IS and restart aborted signal transduction. The same cells are eventually activated to IFN-{gamma} production. Remarkably, under these conditions, IFN-{gamma} production is directly related to the total signaling time despite the periodic interruptions.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
T cells and APCs

A DRB1*0101-restricted human T cell clone 6396p5.1.2 specific for the measles virus fusion protein peptide P5 (F254–268) was used. DR1-matched EBV-transformed human B cells were used as APCs. T cell clones and EBV-B cell lines were generated and maintained as described (5).

Intracellular staining

T cells were conjugated with EBV-B cells as previously described (10). In some samples, cells were treated after 10 min at 37°C with 20 µM PP2 (Calbiochem, San Diego, CA), the drug was kept in culture for additional 10 min, and the cells were rapidly washed and kept for an additional 10 min at 37°C. In additional samples, after 10 min at 37°C the culture medium was changed to mimic the addition of the PP2. After 10 additional min the medium was changed again to mimic the washing of the drug. In a third set of samples cells were treated after 10 min at 37°C with 20 µM PP2 and the drug was left in culture for additional 10 min. The cells were fixed, permeabilized, stained with anti-phosphotyrosine (PTyr) (PY99, Santa Cruz Biotechnology, Santa Cruz, CA) and anti-CD2 mAbs (RPA-2.10, BD PharMingen, Mountain View, CA) and examined using a Carl Zeiss LSM 510 confocal microscope (Carl Zeiss, Jena, Germany) as described (10).

Ca[2+]i analysis

T cells were loaded with 5 µM fura 2-AM (Molecular Probes, Eugene, OR) as described (5). Fura 2-loaded T cells were dropped onto APCs previously pulsed with 10 µM specific peptide and attached on a poly L-lysine-coated slide to form a monolayer in RPMI 5% FCS, 10 mM HEPES. By the means of a perfusion system (Solution exchange system; ALA Scientific Instruments, New York, NY) 20 µM PP2 was cyclically introduced in the chamber and removed by washing with medium. In preparatory experiments the perfusion system was tested using colored media to define the perfusion conditions allowing medium exchange without detaching T cells from the APC monolayer.

Fluorescence measurements were done on a Zeiss axiovert 200 M inverted microscope equipped with a CCD camera (Princeton), an arc-xenon lamp, and a computer-controlled monochromator (T.I.L.L. Photonics, Martinsreid, Germany) at 37°C, 5% CO2. Cells were consecutively excited with 340 and 380 nm at intervals of 10 s by means of the monochromator and both emissions were collected with the CCD camera. The camera output was analyzed using custom calcium-imaging software, MetaFluor, provided by Universal Imaging (West Chester, PA).

ERK phosphorylation analysis

T cells were conjugated with APCs either unpulsed or pulsed with 10 µM specific peptide. Thirty minutes after conjugate formation 20 µM PP2 was added and cells were lysed at different time points after drug addition. Western blot analysis of ERK phosphorylation was performed as described (10).

IFN-{gamma} production

T cells were conjugated with APCs in U-bottom plates at a 1:2 ratio. In some samples 20 µM PP2 were added after 30 min of incubation at 37°C and the cells were kept in culture for additional 120 min. In parallel samples the drug or medium was added 30 min after conjugation, kept for 10 min, and removed by rapid washing. Cells were kept in the absence of the drug for additional 20 min. This cycle was repeated three additional times up to a total incubation time of 150 min. In some experiments the stimulation period was either shorter or longer as indicated in the figure legends. Immediately after termination of the cultures, IFN-{gamma} production was measured by FACS analysis as previously described. (8).


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
The T cell-APC synapse can be destroyed and re-formed

The IS (also named the supramolecular activation cluster, SMAC) is a signaling domain formed at the contact site between T cells and the APCs (11) characterized by large-scale molecular segregation of TCRs, accessory molecules and intracellular signaling components. Even though IS formation is not required to initiate TCR engagement and signaling (12), it is implicated in the control of the quality and extent of biological T cell responses (10).

We attempted to define whether T cells can form multiple IS. T cells were conjugate with APCs pulsed with the specific peptide. After 10 min, the conjugates were treated either with the src kinase-specific inhibitor PP2 or with medium for 10 min. The conjugates were subsequently washed with medium to remove the drug and kept in culture for an additional 10 min (Fig. 1, g–i); medium-cultured conjugates were washed as well and kept in culture for an additional 10 min (Fig. 1, a–c). After fixation and permeabilization, the conjugates were stained with anti-CD2 and anti-PTyr Abs. In control samples conjugates were stained immediately after 10 min of PP2 treatment (Fig. 1, d–f). As Fig. 1, a—c, and Tables I and II show, medium-cultured conjugates exhibited a typical accumulation of synapse markers at the T cell-APC contact site. This accumulation was already detectable in T cell-APC conjugates after 5 min culture as described (10) and was sustained up to at least 1 h (data not shown). In contrast, CD2 and PTyr enrichment at the T cell-APC contact site was suppressed by PP2 (Fig. 1, d–f, Tables I and II). However, upon drug removal and subsequent culturing in medium, CD2 and PTyr were again accumulated at the cellular interface (Fig. 1, g–i, Tables I and II). In control samples we investigated IS formation in T cells interacting with unpulsed APCs. T cells conjugated with unpulsed APCs did not exhibit a recruitment of PTyr or CD2 at the cell-cell contact site in most of the conjugates (in 16% of conjugates a minor increase of either PTyr or CD2 staining was observed, data not shown).



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  		FIGURE 1. IS disruption and reformation in T cell-APC conjugates treated with PP2. T cells were conjugated at 37°C with peptide-pulsed APCs (red) and seeded onto polyL-lysine-coated slides for 10 min before treatment with medium (a–c) or PP2 (g–i) for 10 min. Conjugates were washed with medium and kept in culture for additional 10 min. After fixation and permeabilization, the conjugates were stained for CD2 (green) and PTyr (blue). In parallel samples conjugates were stained immediately after 10 min of PP2 treatment (d–f). a, d, and g, Three color images. In b, e, and h and c, f, and i either the blue or green color has been removed to better show single color staining. Data are from one representative experiment of four.

 

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  		Table I. Measurement of the distribution of CD2 and phosphotyrosines at the ISa

 

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  		Table II. Fold induction of fluorescence intensity at the ISa

 
These results show that the molecular segregation typical for the IS is a consequence of TCR-mediated activation of src kinases. This is in good agreement with previous observations showing that TCR signaling precedes synapse formation (12). Remarkably, our results also demonstrate that, by interfering with TCR-mediated signaling, synapse formation can be rapidly aborted and restarted.

T lymphocytes can be activated by intermittent signals

To understand whether T cells can be activated by interrupted signal transduction, we devised an experimental set up to study the effect of signal interruption in living T cells interacting with APCs. Fura 2 loaded T cells were dropped onto APCs previously pulsed with the specific peptide and attached on a poly L-lysine-coated slide to form a monolayer. Intracellular Ca2+ concentration ([Ca2+]i) was measured, while PP2 was periodically injected and removed with a perfusion system. We added PP2 30 min after dropping the T cells on the APC monolayer (a time sufficient to allow T cells to make contact with the APCs but not sufficient to allow activation to IFN-{gamma} production (8)). The drug was either left in culture throughout the assay (Fig. 2Aa) or left in culture 10 min followed by perfusion with medium (Fig. 2Ab). After washing, the cells were cultured in the absence of the drug for additional 20 min. These cycles of injection and washing were repeated three additional times (Fig. 2Ab).



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  		FIGURE 2. Intermittent signaling results in T cell activation. Aa, Measurement of [Ca2+]i in single T cells untreated (red and blue lines, representative of typical calcium responses) or treated with PP2 after 30 min of conjugation and the drug was left in culture throughout the assay (green an yellow lines). Ab, Measurement of [Ca2+]i in single T cells periodically treated with 20 µM PP2. The white arrow indicates the first addition of the drug, the dotted arrow indicates the first washing of the drug. The same cycle was repeated for three additional times as indicated. The orange arrow indicates the [Ca2+]i baseline. B, At the end of the four cycles of drug addition and washing (150 min), T cell-APC conjugates were fixed, permeabilized and stained with anti-IFN-{gamma} Abs. Overlapping of DIC images with IFN-{gamma} staining (green) is shown. a, Untreated; b, treated with PP2 after 30 min with the drug left in culture; c, periodically treated with PP2. C, Western blot analysis of the kinetics of ERK phosphorylation following treatment with 20 µM PP2. The drug was added either at the time 0 of the stimulation or 30 min after conjugate formation and was left in culture for the indicated times. Data are from one representative experiment of at least three for each panel.

 
The addition of PP2 rapidly blocked calcium mobilization (Fig. 2Aa); conversely the addition and removal of PP2 with the addition of fresh culture medium resulted in abort and restart of the [Ca2+]i increase (Fig. 2Ab).

The cells were then fixed, permeabilized and stained with anti-IFN-{gamma} Abs and inspected by confocal microscopy. In control samples (treated with medium only) T cells conjugated with APCs exhibited a typical polarized secretion of IFN-{gamma} toward the APC (Fig. 2Ba). Interestingly, following periodic treatment with PP2, T cells exhibited a similar IFN-{gamma} polarized secretion (Fig. 2Bc). Conversely if T cell/APC conjugates were treated with 20 µM PP2, 30 min after conjugate formation and the drug was left in culture no IFN-{gamma} production was detected (Fig. 2Bb). Even though confocal microscopy does not allow careful comparison of the total content of intracellular IFN-{gamma} among different individual T cells, the above results indicate that T cells can be activated to IFN-{gamma} production by intermittent signaling.

A possible explanation of the above results could be that other signaling pathways involved in IL production may remain activated during the 10 min treatment with PP2, therefore explaining resistance to periodic addition of the inhibitor. Intracellular calcium mobilization and ERK activation are two signaling pathways know to be strictly required for IFN-{gamma} production in T cells (8, 13), we therefore analyzed ERK activity following treatment with PP2. ERK 1 and 2 phosphorylation was rapidly inhibited following treatment with PP2. It was already reduced after 1 min and was undetectable 5 min after drug addition (Fig. 2C).

Thus both the signaling pathways involved in IFN-{gamma} production (calcium mobilization and ERK activation) are rapidly aborted by treatment with PP2.

Taken together the above results indicate that T cells can be activated to IFN-{gamma} production even though the TCR-mediated signal transduction and the IS formation are periodically aborted. Nevertheless, our data do not exclude the possibility that other T cell responses might be affected by interrupted signaling.

IFN-{gamma} production results from the summation of multiple intermittent signals

It has been shown that T cells interacting with APCs in a collagen matrix can form multiple contacts and become eventually activated to proliferation (7). However, T cell proliferation in collagen matrix is much lower than in liquid cultures and requires high APC/T cell ratios (7). This observation raises the question whether T cells can actually add up packaged signals.

To answer this question we measured IFN-{gamma} production by FACS analysis in T cells cyclically treated with PP2 or with medium only. T cells were conjugated in U-bottom plates with APCs, the inhibitory drug or medium were added to the samples and removed by rapid washing. The same experimental scheme of Fig. 2A was used. The drug was either added 30 min after conjugation and left in the culture throughout the assay, or it was added and removed four times. As shown in Fig. 3A when the drug was added 30 min after conjugate formation and left in culture, a complete inhibition of the IFN-{gamma} production was observed. Conversely, cyclic treatment with PP2 resulted in a moderate inhibition of IFN-{gamma} staining (Fig. 3A). This result is in agreement with the results obtained using the perfusion system (Fig. 2) as it confirms that T cells can be activated by intermittent signaling, yet it also shows that following intermittent signaling T cell activation is reduced. Interestingly, when the T cells periodically treated with PP2 were kept in culture for 40 min longer to allow them to recover the lost signaling time during incubations with the drug, the level of IFN-{gamma} staining was similar to that of control cells (Fig. 3A).



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  		FIGURE 3. IFN-{gamma} production results from the summation of multiple intermittent signals. A, T cells were conjugated with APCs either unpulsed (filled bar) or pulsed with the 10 µM specific peptide (other bars). After 30 min at 37°C the cells were treated with 20 µM PP2 and the drug was left in the culture throughout the assay (open bars). In parallel samples, after initial 30 min incubation the cells were treated either with medium (light gray) or with PP2 (diagonal stripes) for 10 min. After washing, the cells were incubated for 20 min at 37°C in medium. This cycle was repeated for additional three times up to a total time of culture of 150 min. In parallel samples cells cyclically treated with PP2 were cultivated for 40 min longer (total culture time 190 min, dark gray). At the end of the incubation time (either 150 or 190 min), cells were stained with anti-IFN-{gamma} Abs and the median fluorescence intensity of the IFN-{gamma} staining in T cells was measured by FACS analysis. The results are expressed as the percentage of the median fluorescence intensity (MFI) measured in cells treated with medium only. The mean ± SD of the three independent experiments performed in quadruplicate is shown. B, IFN-{gamma} production 90 (open bar), 120 (diamond) and 150 (diagonal stripes) min after conjugate formation in T cells cyclically treated with PP2 using the same experimental scheme of A. Light gray: cells cyclically treated with medium only and stimulated for 150 min. The median fluorescence intensity (MFI) of IFN-{gamma} staining is shown. Data (mean ± SD) are from one representative experiment of three performed in triplicate.

 
The above observation indicated that the extent of T cell activation to IFN-{gamma} production is directly related to the total signaling time irrespectively of periodic disruption of IS; however, it did not prove a summation of interrupted signaling in T cells. To address this issue, we measured the kinetics of IFN-{gamma} production in T cells cyclically treated with PP2 using the same experimental scheme of Fig. 2A. IFN-{gamma} production was measured 90, 120, and 150 min after conjugate formation: each sample was therefore different from the others of a "package" of 30 min (10 min of drug addition plus 20 min stimulation after washing). As shown in Fig. 3B, the addition of each "package" of 30 min resulted in a stepwise increase of IFN-{gamma} production by T cells, demonstrating that T cells can actually add up packaged signals.

The molecular mechanisms of this phenomenon are presently elusive. It is tempting to speculate that one or more signaling intermediates with slow decay can accumulate during T cell activation avoiding the "reset" of the activation process during the interruption of the signaling. It has been proposed that signal summation may occur at the IS, by accumulation of early signaling components during TCR engagement (8, 14). Our results do not exclude this possibility. However, they show that signal summation does not require an intact IS indicating that it may occur outside the IS at some late step of T cell activation.

Taken together our results provide new insights to the understanding of the nature and dynamics of T cell-APC interaction during Ag recognition. Two models of T cell activation that involve either a stable IS or serial encounter between T cells and APCs have been proposed (2, 6, 14, 15). Even though stable synapses are more frequently observed in vitro, it is conceivable that establishment of sequential synapses may also play a role in the control of T cell activation in vivo. For instance, it has been proposed that the rate of serial encounters could dictate whether a naive T cell will be activated or will become anergic during its interaction with dendritic cells in the lymph nodes (16). In addition, also activated T cells may need to establish multiple contacts in vivo as part of their immune-surveillance role (6).

Recent studies performed with lymphoid organs using either conventional confocal microscopy or two-photon confocal microscopy came to opposite conclusions. In a first study the interaction between T cells and APCs in isolated lymph nodes appeared to be relatively static and long lasting (17). In a second study naive T cells appeared highly mobile and formed dynamic contacts with APCs while migrating through lymphoid tissue (18). In the present in vitro study we use a complementary experimental approach. Although we do not disrupt T cell-APC interaction, we repeatedly destroy the IS and abort the signaling pathways required for IFN-{gamma} production. By measuring the synthesis of this cytokine we show that T cell activation can result from summation of interrupted signaling.

Our results do not settle whether T cell interaction with APCs is actually stable or intermittent. However, they strongly suggest that a "polygamous" T cell can indeed add packaged signals and become correspondingly activated.


   Acknowledgments
 
We thank Paola Romagnoli, Lucette Pellettier, and Clemens Utzny for critical reading and discussion of the manuscript.


   Footnotes
 
1 This work was supported by grants from Institut National de la Santé et de la Recherche Médicale, from la Ligue contre le Cancer and from the fondation Banque National de Paris-Parisbas. Back

2 Address correspondence and reprint requests to Dr. Salvatore Valitutti, Institut National de la Santé et de la Recherche Médicale Unité 563, Institut Claude de Préval, Centre Hospitalier Universitaire Purpan, 31059 Toulouse Cedex 3, France. E-mail address: svalitu{at}toulouse.inserm.fr Back

3 Abbreviations used in this paper: IS, immunological synapse; PTyr, phosphotyrosine; [Ca2]i, intracellular Ca2 concentration. Back

Received for publication March 4, 2003. Accepted for publication June 4, 2003.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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