Antigen-dependent and -independent Ca2+ Responses Triggered in T Cells by Dendritic Cells Compared with B Cells

Delon, Jérôme; Bercovici, Nadège; Raposo, Graça; Liblau, Roland; Trautmann, Alain

doi:10.1084/jem.188.8.1473

Cited by 140 publications

(148 citation statements)

References 52 publications

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“…Antigen presentation by B cells has been shown to induce tolerance [24,31], and resting B cells are known to play essential roles in transplantation tolerance and tolerance against tumors in a MHC-class II dependent manner [32][33][34]. Unlike DC, B cells are APC that do not constitutively express high levels of co-stimulatory molecules like MHC class II and B7 [35]. B cells are therefore thought to induce anergy in T-cells by providing only the first signal for T-cell activation [23,24].…”

Section: Discussionmentioning

confidence: 99%

Resting B cells expand a CD4⁺CD25⁺Foxp3⁺ Treg population via TGF‐β3

Shah

Qiao

2008

Eur J Immunol

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Regulatory T cells (Treg) play critical roles in maintaining tolerance and preventing autoimmunity. It is not fully clear how these cells are generated and maintained. Here, we show that resting B cells are able to expand Treg. This expansion requires TGF-b3 and signaling through the TCR and CD28. Upon activation, B cells express less TGF-b3, which reduces their capacity to expand Treg and which also results in increased Treg death. This may ensure that B cells can function as potent professional antigen presenting cells during infections. However, in the absence of any infection, we find that B-cell-deficient lMT mice have decreased percentages of Treg in the periphery. Our data suggest that resting B cells, which may be presenting self-antigens to T cells, can expand and maintain specific Treg and thus might be involved in the prevention of autoimmunity. Key words: B cells . Regulatory T cells . Tolerance Supporting Information available online IntroductionRegulatory T cells (Treg) are a subset of T cells that can actively suppress innate as well as adaptive immunity and have been implicated in self-tolerance, autoimmunity, cancer, transplantation immunology and a myriad of infectious diseases [1][2][3][4][5][6]. There are numerous different subsets of Treg based on their phenotypic markers, amonge which the naturally occurring Treg (nTreg) population is well studied and characterized. nTreg are a subset of CD4 1 T cells expressing CD25 and the transcription factor Forkhead box protein 3 (Foxp3). Foxp3 has been shown to be the master regulator for the generation of nTreg. Although Foxp3 À/À mice lack CD4 1 CD25 1 T cells, expression of Foxp3 in CD4 1 CD25 -T cells is sufficient for converting them into CD4 1 CD25 1 T cells with suppressive function [7,8].CD4 1 CD25 1 Foxp3 1 Treg arise in the thymus and enter into the periphery where they constitute $5-10% of the CD4 1 T cells. nTreg generation in the thymus is thought to require high-affinity peptide-MHC class II interactions in contrast to low-affinity peptide-MHC class II interactions required for positive selection of conventional CD4 1 T cells [9,10]. There are also strong evidences for the generation of CD4 1 CD25 1 Foxp3 1 Treg in the periphery. Experiments carried out in thymectomized or RAG-2-deficient mice lacking CD4 1 CD25 1 T cells show that nTreg can be generated in the periphery from CD4 1 CD25 À T cells [11,12].In addition to co-stimulation via the B7-CD28 and TCR-MHC class II pathways, various cytokines such as IL-2, TGF-b1 and IL-10 have been associated with the generation of peripheral Treg. IL-2 and IL-2R knockout mice have few, if any, nTreg and develop severe lymphoproliferation and autoimmunity [13,14]. TGF-b1 or IL-10 have been shown to expand Treg and even convert CD4 1 CD25 À T cells into CD4 1 CD25 1 T cells with suppressive functions [13,[15][16][17][18].Antigen presenting cells (APC) express both MHC class II as well as B7 molecules and secrete cytokines that may modulate the differentiation of T cells into either T-effector or T-r...

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Section: Discussionmentioning

confidence: 99%

Resting B cells expand a CD4⁺CD25⁺Foxp3⁺ Treg population via TGF‐β3

Shah

Qiao

2008

Eur J Immunol

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“…These Ag-free synapses are characterized by the accumulation of CD3, CD4 or CD8, talin, CD45 and phosphotyrosine, and by the relocation of the centrosome towards the IS. In one previous study on the IS formed between T cells and DC, the EM data showed no indication in favor of the existence of a c-SMAC [13], but this point was not completed by IF data, or by a thorough ultrastructural analysis. Given the physiological importance of this synapse, we decided to examine more closely its structure, both in the presence and in the absence of exogenous Ag.…”

Section: Introductionmentioning

confidence: 86%

“…To examine if the structure observed after 15 min of T-DC interaction was a transient one, we also analyzed IS after 30 min of T-DC interaction. Given the high efficiency of DC as APC and the short delay between T-DC contact and the triggering of a Ca 2+ responses [13], 30-min-old T-DC conjugates cannot be considered as being in a transient state of synapse formation. In these older synapses, the distribution of CD3 and LFA-1 was strikingly similar to the one observed after 15 min of interaction, i.e.…”

Section: The Multifocal Pattern Is Not a Transient State Of T-dc Synamentioning

confidence: 99%

“…Despite its exceptional physiological importance, the IS formed between T cells and DC has been little studied, except in a few papers where the existence of T-DC synapses in the absence of exogenous Ag was demonstrated [13,14]. These Ag-free synapses are characterized by the accumulation of CD3, CD4 or CD8, talin, CD45 and phosphotyrosine, and by the relocation of the centrosome towards the IS.…”

Section: Introductionmentioning

confidence: 99%

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Multifocal structure of the T cell - dendritic cell synapse

et al. 2005

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The structure of immunological synapses formed between murine naive T cells and mature dendritic cells has been subjected to a quantitative analysis. Immunofluorescence images of synapses formed in the absence of antigen show a diffuse synaptic accumulation of CD3 and LFA-1. In electron microscopy, these antigen-free synapses present a number of tight appositions (cleft size *15 nm), all along the synapse. These tight appositions cover a significantly larger surface fraction of antigen-dependent synapses. In immunofluorescence, antigen-dependent synapses show multiple patches of CD3 and LFA-1 with a variable overlap. A similar distribution is observed for PKCh and talin. A concentric organization characteristic of prototypical synapses is rarely observed, even when dendritic cells are paralyzed by cytoskeletal poisons. In T-DC synapses, the interaction surface is composed of several tens of submicronic contact spots, with no large-scale segregation of CD3 and LFA-1. As a comparison, in T-B synapses, a central cluster of CD3 is frequently observed by immunofluorescence, and electron microscopy reveals a central tight apposition. Our data show that it is inappropriate to consider the concentric structure as a "mature synapse" and multifocal structures as immature.

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“…In vitro imaging systems that combine BRIGHT-FIELD MICROSCOPY or NOMARSKI OPTICS with FLUORESCENCE MICROSCOPY have been particularly good at revealing the individual behaviours and interactions of cells in the immune system. Previous in vitro studies that visualized T cells interacting with antigenpresenting cells (APCs), or beads used as surrogate APCs, have shown dynamic changes in Tcell motility, shape, contact requirements, intracellular calcium signalling (through FURA-2 RATIOMETRIC IMAGING) and reporter gene expression [1][2][3][4][5][6][7] (FIG. 1).…”

Section: Imaging T-cell Dynamics In Vitromentioning

confidence: 99%

Two-photon tissue imaging: seeing the immune system in a fresh light

et al. 2002

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Many lymphocyte functions, such as antigen recognition, take place deep in densely populated lymphoid organs. Because direct in vivo observation was not possible, the dynamics of immune-cell interactions have been inferred or extrapolated from in vitro studies. Two-photon fluorescence excitation uses extremely brief (<1 picosecond) and intense pulses of light to 'see' directly into living tissues, to a greater depth and with less phototoxicity than conventional imaging methods. Twophoton microscopy, in combination with newly developed indicator molecules, promises to extend single-cell approaches to the in vivo setting and to reveal in detail the cellular collaborations that underlie the immune response.Scientific questions drive the development of technology, and new technologies, in turn, influence the type of questions that we pose in an iterative process of discovery. Applied to immunology, this has prompted the innovation and application of powerful techniques for analysing the microscopic world of the immune system. Two methodological lines of investigation have dominated the field: in vivo experiments that examine the behaviour of populations of cells in living animals during an immune response; and in vitro experiments that use individual cells in artificial environments. An immune response is the sum of many complex and dynamic individual cellular behaviours that are shaped by many environmental factors. In vivo experiments maintain this natural environment, but they cannot resolve the behaviours of individual cells. By contrast, in vitro experiments provide information at the subcellular and molecular levels, but they cannot replicate adequately the full repertoire of environmental factors. There is a pressing need for techniques that allow real-time observation of single cells and molecules in intact tissues. Recent developments in imaging technology now make this possible. In this review, we provide a guide to the application of biophotonic techniques to the field of immunology and, in particular, to the use of two-photon laser microscopy. We discuss recent results obtained using this approach and pinpoint some key questions that might be resolved by tissue imaging. The biophotonics tool kitImmunologists have long been adept at raiding other disciplines to acquire new research tools. Fluorescence techniques -for example, flow cytometry, video imaging and more exotic imaging modalities, such as FLUORESCENCE RESONANCE ENERGY TRANSFER (FRET) and two-photon microscopy -combined with new probes to track Ca 2+ signalling, Correspondence to M.D.C. mcahalan@uci.edu. NIH Public Access Imaging T-cell dynamics in vitroThe single-cell approach has intrinsic value, because asynchronous behaviours are not indicated by population measurements. The need for live-tissue imagingIn vivo approaches have elucidated the basic properties of immune cells and lymphoid tissues, whereas in vitro cell-culture systems have provided a high-definition analysis of the cellsurface receptors and intracellular signalling pat...

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Antigen-dependent and -independent Ca2+ Responses Triggered in T Cells by Dendritic Cells Compared with B Cells

Cited by 140 publications

References 52 publications

Resting B cells expand a CD4⁺CD25⁺Foxp3⁺ Treg population via TGF‐β3

Resting B cells expand a CD4⁺CD25⁺Foxp3⁺ Treg population via TGF‐β3

Multifocal structure of the T cell - dendritic cell synapse

Two-photon tissue imaging: seeing the immune system in a fresh light

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Antigen-dependent and -independent Ca2+ Responses Triggered in T Cells by Dendritic Cells Compared with B Cells

Cited by 140 publications

References 52 publications

Resting B cells expand a CD4+CD25+Foxp3+ Treg population via TGF‐β3

Resting B cells expand a CD4+CD25+Foxp3+ Treg population via TGF‐β3

Multifocal structure of the T cell - dendritic cell synapse

Two-photon tissue imaging: seeing the immune system in a fresh light

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Resting B cells expand a CD4⁺CD25⁺Foxp3⁺ Treg population via TGF‐β3

Resting B cells expand a CD4⁺CD25⁺Foxp3⁺ Treg population via TGF‐β3