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T Lymphocytes
Departments of
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Immunology, and
Oncology and Signalisation dans les Cellules Hématopoïétiques, Unité 563, Institut National de la Santé et de la Recherche Médicale, Centre Hospitalier Universitaire de Purpan, Toulouse, France; and
Institut National de la Santé et de la Recherche Médicale, Unité 463, Nantes, France
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Abstract |
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9V
2 TCR recognize non-peptidic Ags, referred to as phosphoantigens, produced by microbial pathogens and by human tumor cells. Here we show that T cells establish a mature immunological synapse (IS) with the myelomonocytic THP-1 tumoral cell line. This synapse is characterized by an enrichment for phosphotyrosine, CD2, and TCR together with the exclusion of CD45. The CD94 and NKG2D receptors are also recruited to the signaling area, while the C-lectin-like activation marker CD69 segregates out of the synapse. T cell conjugation to THP-1 increases upon stimulation by soluble phosphoantigen, is paralleled by the metabolic activation of T cells and leads to cytokine production. Molecular segregation of the above molecules also occurs at the T cell/THP-1 interface in the absence of exogenously added phosphoantigen, although it does not result in intracellular signaling and cytokine production under these conditions. Hence the molecular interactions at the T cell-THP-1 target cell interface are sufficient to induce the formation of an IS, but cytokine production requires the full engagement of TCR by a strong agonist. Thus in T cells, formation of the IS is uncoupled from its functional outcome. |
Introduction |
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T cells comprise a major subset of mostly double negative (CD4-CD8-) phenotype, which expresses V9V2-encoded TCRs and some NK-lineage receptors for MHC class I (reviewed in Ref. 1). Although these cells present the hallmark of adaptive immunity by producing clonally distributed TCR by somatic recombination of V, D, J, and C gene segments, they also show typical features of innate immunity.
On the one hand, TCR V9V2 lymphocytes spontaneously recognize in the absence of MHC-presenting molecule a structurally related set of hydrosoluble Ags referred to as phosphoantigens, alkylamines, and aminobisphosphonates (reviewed in Ref. 2). Recognition of these non-peptide Ags strictly depends on TCR interactions involving amino acid residues located on both the V9- and V2-CDR3 regions (3, 4, 5). In some conditions, soluble phosphoantigens can induce TCR-mediated signaling without down-modulation of the Ag receptor, indicating that some aspect of TCR signaling may differ from signal transduction mediated by 
TCR (6, 7). Although no presenting molecule seems required, phosphoantigen-induced V9V2 lymphocytes activation requires cell-cell contact (8). V9V2 lymphocytes also react against a variety of virally infected-, activated-, or tumor cells (9), in the latter case upon specific recognition of phosphoantigenic metabolites derived from their endogenous mevalonate pathway (10).
V9V2 T cells frequently express NK receptors for self-MHC or MHC-like structures, which comprise both activatory (e.g., NKG2D) and inhibitory (e.g., CD94/NKG2A, B) receptors. The activatory NKG2D, a lectin-like homodimer associated to the DAP-10 adaptor, recognizes stress-induced self-ligands such as MIC or ULBP proteins (11, 12). Upon engagement by MHC class I chain related gene a (MICA)3-B and ULBP, NKG2D delivers an activating signal by recruiting phosphatidylinositol-3-kinase (13). NKG2D-triggered signaling induces the full cytolytic response of NK cells (14, 15, 16). In other cell types such as T lymphocytes however, this results in a costimulus enhancing TCR-induced responses of (17) and T lymphocytes (18, 19). MIC proteins are expressed by keratinocytes, endothelial cells, and monocyte cell lines including Th precursor (THP)-1 cells (20). By contrast, the heterodimeric CD94/NKG2A,B receptors deliver inhibitory signals upon recognition of HLA-E on target cells (21). These inhibitory receptors are expressed at the cell surface of most circulating human T cells (22). By modulating the activation threshold of T cells, these inhibitory NK cell receptors (NKR) fine-tune their autoreactivity (23), as well as their antiviral (24) and anti-tumor activity (25). While the biological function of T cells is now better understood, the molecular dynamics occurring at the contact site between T cells and their targets are still elusive. Recent work has documented the ability of human V9V2 lymphocytes stimulated by soluble or cellular Ags to acquire membrane markers from their conjugated targets (26). This activity of lymphocytes corresponds to a synaptic transfer, but yet the molecular structure of the immunological synapse (IS) has not been defined. Molecular transfer from target cells has already been described in T and B lymphocytes, in NK cells, in dendritic cells (reviewed in Ref. 27, 28) where it occurs after formation of the IS.
It is well established that in T cells, the process of Ag recognition involves the formation of an IS (29, 30, 31, 32). This area focalizes a complex molecular reorganization that results in a localized intracellular signaling. A mature IS is characterized by a central supramolecular cluster of TCR and accessory molecules (33), whereas large molecules such as LFA-1, CD43, and CD45 are localized at the periphery (34, 35, 36, 37, 38). TCR engagement precedes the formation of the mature IS, which gradual formation is initiated by TCR-signaling at the periphery of the cell-cell interface (39). These observations suggest that IS formation is more a consequence than a pre-requisite for TCR engagement and signaling. Conversely, it has been recently shown that, in resting T cells interacting with dendritic cells, IS formation may occur in the absence of both antigenic peptide and MHC molecules (40). This observation contrasts with previous results, obtained using activated T cells, and raises the question of whether a re-organization of accessory molecules and signaling components may predispose T cells to Ag recognition. Thus, the functional role of the IS in T lymphocytes is still elusive. It may serve several non-mutually exclusive functions. The IS could augment and sustain the activation of signaling pathways (31, 41), favor polarized cytokine secretion (42), or rather enable TCR down-regulation (39).
In the present work, we provide the first description of the molecular structure of the IS in T cells. For this study, we used V9V2 T lymphocytes conjugated to the MICA expressing myelomonocytic cell line THP-1, either in the absence or presence of added soluble phosphoantigen. This model was selected for its unique opportunity to cumulate in a single target cell type: 1) the ability to associate phosphoantigens (5), 2) the surface expression of NKG2D ligands (20), 3) which spontaneously leads to strong conjugation with human V9V2 T lymphocytes, as recently detected by synaptic transfer (26), and 4) which conjugation is modulated by either exogenous phosphoantigen or PP2 inhibitor (26). The localization of different markers of the IS at the cell-cell contact site was visualized by confocal microscopy. We report that while T cells spontaneously form a mature IS with THP-1 cells regardless of exogenous phosphoantigen addition, this latter is required to fully trigger T cell cytokine responses.
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Materials and Methods |
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Polyclonal V9V2 T cell lines were specifically raised by incubating PBL derived from healthy donors (106/ml) in culture medium with the mycobacterial compound 3-formyl-1-butyl-pyrophosphate (10 nM (43)) plus 100 U/ml rh-IL2 (Sanofi-Synthélabo, Lab
ge, France) during 20 days. The expansion of V9V2 T cells was followed by cytometric analysis and only cultures showing >95% TCR V2 positive cells were used for subsequent experiments. The G12 V9V2 T cell clone has been described in (22). The MICA-positive THP-1 cell line (20) was cultured in RPMI 1640 complete culture medium plus 2-ME (50 µM). When specified, the synthetic phosphoantigen agonist bromohydrin pyrophosphate (BrHPP (44)) was added to the cultures at the concentrations specified in the text.
Microphysiometry
Microphysiometry experiments involving cells were measured using a Cytosensor (Molecular Devices, Wokingham, U.K.) as already described (44).
Confocal microscopy
T cells were conjugated with THP-1 cells previously loaded for 10 min at 37°C with 0.5 µM Orange-CMTMR Cell Tracker or 0.5 µM Green-CMFDA Cell Tracker (Molecular Probes, Leiden, The Netherlands). In some experiments, synthetic BrHPP was added into the medium at a final concentration of 100 nM just before making conjugates. After 30 min incubation at 37°C, the cells were gently resuspended and laid on poly-L-lysine-coated slides for 5 min at 37°C. Cells were fixed and permeabilized as described previously (37). Stainings were realized with anti-phosphotyrosine (P-Y) mAbs (Santa Cruz Biotechnology, Santa Cruz, CA) and with either anti-CD2 (HB222, ATCC) or anti-CD45 (10G10 kindly provided by F. Spertini), or anti-TCRV9 (Beckman Coulter, Marseille, France), or anti-NKG2D (Clone ON 72, kindly provided by Dr A. Moretta) or anti-CD94 mAbs (HP3-BA, Beckman Coulter) or anti-CD69 (Beckman Coulter) followed by Rhodamine-labeled goat anti-mouse Abs (Beckman Coulter) or by Cy5-labeled goat anti-mouse Abs (Caltag Laboratories, Burlingame, CA) and FITC-labeled goat anti-mouse Abs (Southern Biotechnology Associates, Birmingham, AL) as described (37). For IFN- or TNF- staining (both Abs from BD PharMingen, San Diego, CA), the cells were fixed as above and permeabilized with saponin after 120 min incubation of conjugates at 37°C as described (45). The samples were mounted and examined using a Carl Zeiss LSM 510 confocal microscope (Zeiss, Jena, Germany).
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Results |
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T cells form IS with THP-1 both with and without adding soluble phosphoantigen.
We used confocal microscopy to investigate the structure of ISs formed by a human polyclonal V9V2 T cell line when conjugated to myelomonocytic THP-1 cell line either in the presence or absence of the synthetic BrHPP phosphoantigen. The cytoplasm of THP-1 cells was stained orange with 5-(and-6)-(((4-chloromethyl) benzoyl) amino) tetramethyl rhodamine and visualized in red for discrimination from T cells. T cells formed conjugates with THP-1 cells regardless of the presence of the exogenous phosphoantigens; however the number of conjugates was increased when BrHPP was present in the culture (not shown). Staining with anti-P-Y Abs revealed clustering of P-Ys in T cells at the contact site with THP-1 cells. Surprisingly, this clustering was readily observed in the absence of phosphoantigen, although it was more pronounced and occurred more frequently in BrHPP-stimulated cells (Fig. 1 and Table I). We next studied the CD2 and CD45 localization at the T cell/target cell contact site. CD2 was enriched at the T cell surface in contact with THP-1 cells and colocalized with P-Ys (Fig. 1A). By contrast, the CD45 phosphatase was excluded from the central part of the T cell IS (Fig. 1B). Finally, the adhesion molecule LFA-1 segregated at the border of the cell-cell interface (data not shown). All the above described morphological hallmarks of mature IS were observed both in the absence and the presence of BrHPP, although they were more frequent in phosphoantigen-activated-conjugates than in unstimulated ones (Table I). The above data suggested that addition of the BrHPP phosphoantigen to the cultures provided an additional stimulation signal for the T cells, presumably delivered by the V9V2 TCR. To address this point, we costained V9V2 TCR and P-Ys both in a polyclonal V9V2 T cell line (Fig. 2A) and in a V9V2 T cell clone (Fig. 2B) forming conjugates with THP-1 cells with or without BrHPP. In the absence of phosphoantigen, a relatively small fraction of conjugates showed TCR enrichment that colocalized with P-Ys at the IS (Table I). This phenotype was observed twice more frequently in corresponding cultures with BrHPP (Fig. 2A and Table I). Similar results were obtained with both monoclonal and polyclonal V9V2 T cells, excluding the possibility that they were due to a peculiar reactivity of a particular cell subset (Fig. 2, A and B).
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T cells exhibit an IS similar to that previously described for T cells (29, 30, 31, 32). Remarkably, they also show that a significant large scale molecular segregation already occurs at the V9V2 T cell/THP-1 cell interface in the absence of a soluble TCR stimulus.
NKRs are recruited within the T cell IS independently from phosphoantigen addition
Most human V9V2 T lymphocytes express the activating cell surface immunoreceptor NKG2D which delivers a costimulation signal (18). We therefore assessed the localization of NKG2D in V9V2 T cell/THP-1 conjugates. NKG2D was recruited to the IS in the majority of T cells conjugated with THP-1 even in the absence of phosphoantigen (69% of conjugates, Fig. 3A and Table I). Interestingly the frequency of conjugates exhibiting enrichment for NKG2D at the cell-cell contact site was not significantly increased by addition of BrHPP (Fig. 3A and Table I).
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70% resting peripheral blood human V9V2 T lymphocytes (22, 24). We next investigated the localization of CD94 in the T cell/THP-1 synapse. CD94 was enriched within the IS in 28% of THP-1 cell conjugates in the absence of phosphoantigens (Table I and Fig. 3B). In the presence of BrHPP the frequency of IS enriched for CD94 was increased (55% of positive conjugates, Table I).
These results show that two members of the NKR family known to modulate T cell biological responses are recruited to the IS formed between V9V2 T cells and THP-1 both in the presence and in the absence of BrHPP.
Formation of the T cell synapse with THP-1 is associated with exclusion of the CD69 activation marker
Taken together, the above findings showed that a significant fraction of T cells recruited both inhibitory and activatory NK receptors in addition to the V9V2 TCR at their IS with targets. Both THP-1 and T cells used here expressed the early activation marker CD69 (data not shown). We wondered whether this NKR family member was also involved in the formation of IS. Surprisingly, CD69 was found excluded from most of the THP-1/V9V2 T cell synapses in presence of BrHPP phosphoantigen (Fig. 3C and Table I). The analysis of synapses formed in absence of Ag revealed CD69 exclusion to a lesser extent (Table I). Thus, formation of the IS by T cells involves exclusion of the CD69 homodimer at the cells contact area.
TCR engagement by phosphoantigen is required for cytokine-polarized secretion
Taken together, the above findings show that a significant fraction of T cells formed mature IS with THP-1 cells in the absence of TCR engagement by a strong exogenous ligand. We therefore investigated whether functional responses such as polarized release of cytokines could also be observed in the absence of this soluble ligand. The T cell/THP-1 cocultures were stained for IFN- and TNF-, two major cytokines produced by activated T cells (8, 18, 44). When BrHPP was added to the cultures, a large fraction of T cells conjugated with target cells exhibited polarized expression of IFN- and TNF- at the contact site with THP-1. Conversely, conjugates formed in medium alone did not exhibit detectable staining for cytokines (Fig. 4A). These results were paralleled by the observation that an increase in the metabolic rate of T cells was observed only after addition of BrHPP to T cell cultures (Fig. 4B). Accordingly, the same polyclonal V9V2 T cells released in the culture medium both IFN- and TNF- in a dose-dependent fashion only when exposed to BrHPP (data not shown).
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T cells and THP-1 cells in the absence of phosphoantigen are not functionally productive. Thus, they imply that T cells require strong engagement of TCR to induce full-blown activation of their effector functions. |
Discussion |
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T lymphocytes represent effector cells at the crossroads between innate and adaptive immunity (1). Here we report the first characterization of the T cell IS. We show that in these cells, large scale molecular segregation occurs, similarly to T cells (37). Surface molecules with large extracellular domains such as CD45 and LFA-1 are excluded from the center of the IS whereas conversely CD2 and P-Y activation markers colocalize at this central area. In addition, the NKRs are also recruited at the center of the T cell IS. CD69 is another molecule belonging to the NK genes complex. It is also known as a marker of early activation closely related to the CD94 molecule (46). Cytometry analysis had shown that all T cell lines used here express CD69 (data not shown), as expected from the culture conditions used for raising these cells. Unexpectedly, this C-type lectin-like stimulatory and costimulatory activation marker (47) was predominantly excluded from the IS.
What could account for segregation of this activation marker? It appears most likely that the exclusion of this homodimeric receptor, which extracellular domain spans over 7 nm (48), does not hinder the 15 nm distance set between the apposing membranes. Instead, this segregation could presumably reflect the exclusion of its so far unknown ligand. The physiological relevance of this phenomenon is not obvious because stimulation with anti-CD69 Abs induces intracellular activating signaling events in different hematopoietic cell types (49, 50, 51). Nevertheless, a recent study using CD69-/- mice has shown that CD69 acts as a negative regulator of anti-tumor responses (52). Thus physiological setting of the IS may require CD69 exclusion.
The IS between T cells and THP-1 cells was stable for up to 1 hr (data not shown), as reported for ISs of T cells (29). This stability is consistent with the time required for performing the synaptic transfer recently documented in T cells (26). Interestingly, the T cell IS was not restricted to cells stimulated by the strong TCR agonist BrHPP. It also occurred in THP-1 conjugates formed without adding any exogenous ligand. In addition, the accumulation of P-Ys at the cell-cell interface underlines an activation process already initiated in the absence of phosphoantigen. This signaling may either result from the engagement of TCRs by cellular ligands such as endogenous phosphoantigens (10), or from the engagement and signaling of other cell surface receptors. Accordingly, we observed that while the CD45 phosphatase was excluded, CD2, NKG2D, and CD94 molecules were enriched at the cell-cell contact site irrespective of phosphoantigen addition. In naive T lymphocytes interacting with dendritic cells as well, reorganization of accessory molecules and P-Y signaling takes place without involving antigenic ligand to enable naive cells survival (40).
However, IS formation and signaling in activated T cells requires TCR engagement by peptide agonist ligands, underlining a major difference between and T cell IS. In addition to the large scale segregation of accessory molecules without exogenous TCR ligand, other features distinguish human activated from T cell synapses. Contrarily to observations drawn from T cell models, here, only a minority of conjugated T cells exhibited TCR enrichment at the contact site with THP-1 cells. This was true regardless of the presence of the phosphoantigen in the cell cultures. Together with the observation that TCRs barely down-modulate upon engagement (6, 7), our results indicate that TCR recruitment and signaling may proceed differently in and T cells. A third salient feature of the T cell IS described here is that, while in activated T cells the formation of a mature IS correlates with full activation of the biological response, IS formation and activation appear to be uncoupled in T cells. Indeed, the early signaling at the T cell synapse is functionally dissociated from the cytokine secretion in conjugates formed without Ag (Figs. 3 and 4). Consistent with non-productive interactions with THP-1 cells, the V9V2 cells did not significantly kill THP-1 cells nor secrete Th-1 cytokines in the absence of exogenously added BrHPP (data not shown). It is tempting to speculate that in T cells, a non-productive but mature synapse may be formed through Ag-independent interactions between activating molecules such as NKG2D or CD2 and their respective ligands. This model is supported by the CD69 exclusion from the spontaneous IS with THP-1 that we describe here for the first time. Additional signals derived from TCR engagement by a strong ligand appear to upraise the basal activation signals delivered by the accessory molecules, achieving full metabolic activation and ultimately, lead to cytotoxic response and cytokine production. So, phosphoantigens may provide the complementary TCR-induced stimulus to reach the activation threshold needed to trigger cytokine production. In this respect, our results are in good agreement with earlier data showing that exogenous supply of phosphoantigen increases calcium mobilization in conjugated T cells but not in isolated cells (53).
Since we observed a significant recruitment of accessory molecules and even of TCR (but not CD69) to the IS of T cells in the absence of phosphoantigen, why TCR engagement by a strong, soluble ligand is required to activate the biological response?
Possible explanations would be that the low amounts of endogenous phosphoantigens produced by the THP-1 target cells (10) and/or adhesion molecules plus MICA-NKG2D engagements enable the above-mentioned synaptic reorganization. However, inhibitory NKR expressed at the cell surface of most peripheral blood T cells are also recruited to these "spontaneous" IS. Since these inhibitory receptors contribute to strongly reduce the activating signals (22, 23, 24), their recruitment at the T cell IS most likely set a higher threshold for the triggering of biological responses. In this regard, the exogenous supply of high amounts of BrHPP produces a strong TCR engagement which definitively reaches this activation threshold, triggers positive intracellular signaling and leads to sustained metabolic activation (7).
In conclusion, our results are compatible with the following functional role of IS in T cells. In the initial steps of T cell interaction with target cells, the formation of IS might be mediated by the engagement of both TCR and NKRs followed by "borderline" signaling. This early synapse serves to set the activation thresholds of T cells. Indeed, we assume that the inhibitory NKR interactions with protective HLA alleles strongly shift the balance in favor of negative signaling, thus inhibiting T cell activation along homotypic cell synapses. In the cellular system analyzed here however, the signals emanating from activating receptors overpassed negative signals as IS were spontaneously formed without adding phosphoantigen. Upon strong TCR engagement by phosphoantigen though, the bound T lymphocytes reach and maintain a full activation status leading to their polarized secretion of cytokines. So here, IS formation induced by innate immunity receptors (NKRs) modulate the signaling of adaptative immunoreceptors ( TCRs) from the same cells. Obviously, each conjugate between a T cell and another cell target will determine a open set of interactions between surface receptors interacting with their ligands from the target, within the IS or at its periphery. Thus depending on the nature of the ligands displayed by the scanned targets, qualitatively and functionally different synapses may be formed, but describing these was far out of reach for this first description of the T cell IS. Here, the IS between a monocytic cell target and T cells derived from healthy donors underline the role of innate receptors in tuning the adaptive immune responses of T lymphocytes. Future studies from our laboratory will now aim at describing IS between T cells and autologous tumor cell targets from cancer patients.
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Acknowledgments |
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Footnotes |
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2 S.V., and J.-J.F. contributed equally to this work
3 Address correspondence and reprint requests to Dr. Jean-Jacques Fournié, Département Oncogense and Signalisation dans les Cellules Hématopoïétiques, Unité 563, Institut National de la Santé et de la Recherche Médicale, BP3028, Centre Hospitalier Universitaire de Purpan, 31024 Toulouse, France. E-mail address: fournie{at}toulouse.inserm.fr
4 Abbreviations used in this paper used: MICA, MHC class I chain related gene a; THP, Th precursor; NKR, NK cell receptors; IS, immunological synapse; BrHPP, bromohydrin pyrophosphate; P-Y, anti-phosphotyrosine.
Received for publication March 3, 2003. Accepted for publication September 5, 2003.
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