T cell killing does not require the formation of a stable mature immunological synapse

Purbhoo, Marco A.; Irvine, Darrell J.; Huppa, Johannes B.; Davis, Mark M.

doi:10.1038/ni1058

Cited by 514 publications

(499 citation statements)

References 36 publications

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“…What this might be is suggested by the fact that these invasive pseudopodia would significantly increase the surface area of T cell-APC contact, at least fivefold over a "flat" interaction, thus enabling the T cell to sample much more of the possible antigens on the APC surface. T cells are very sensitive to their peptide-MHC ligands, able to detect even one molecule (32,33), and although this is sufficient for the cell to stop, more peptide-MHC agonist ligands are usually needed (3)(4)(5)(6)(7)(8)(9)(10) to make a full response (2). Interestingly, this remarkable probing activity has not been seen in fluorescence studies of T cell-APC interactions, perhaps because of a lack of resolution and/or its rapidity.…”

Section: Discussionmentioning

confidence: 99%

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CD4⁺T-cell synapses involve multiple distinct stages

Ueda

Morphew

McIntosh

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

114

109

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One very striking feature of T-cell recognition is the formation of an immunological synapse between a T cell and a cell that it is recognizing. Formation of this complex structure correlates with cytotoxicity in the case of killer (largely CD8 + ) T-cell activity, or robust cytokine release and proliferation in the case of the much longer lived synapses formed by helper (CD4 + ) T cells. Here we have used electron microscopy and 3D tomography to characterize the synapses of antigen-specific CD4 + T cells recognizing B cells and dendritic cells at different time points. We show that there are at least four distinct stages in synapse formation, proceeding over several hours, including an initial stage involving invasive T-cell pseudopodia that penetrate deeply into the antigen-presenting cell, almost to the nuclear envelope. This must involve considerable force and may serve to widen the search for potential ligands on the surface of the cell being recognized. We also show that centrioles and the Golgi complex are always located immediately beneath the synapse and that centrioles are significantly shifted toward the late contact zone with either B lymphocytes or bone marrow-derived dendritic cells such as antigenpresenting cells, and that there are dynamic, stage-dependent changes in the organization of microtubules beneath the synapse. These data reinforce and extend previous data on cytotoxic T cells that one of the principal functions of the immunological synapse is to facilitate cytokine secretion into the synaptic cleft, as well as provide important insights into the overall dynamics of this phenomenon. microtubule organizing center | centrosome A prominent feature of many T-lymphocyte interactions with other cells on which it recognizes a particular antigen is the formation of an immunological synapse (IS). The formation of this structure correlates with robust signaling, lineage commitment, and fate determination of T cells (1-6) and the directed secretion of cytokines and/or cytotoxic molecules. There is a wholesale reorganization of the T cell's cytoskeleton, surface molecules, and organelles, and the loss of polarity regulators or guidance cues that negatively affect T-cell activation (7,8). Whereas a great deal has been learned about the dynamics of cell-surface and signaling molecules within this interface (9, 10), much less is known about changes within the cell, especially in the long-lived helper T cell, namely in antigen-presenting cell (APC) interactions, which can last for 6 or more h and need continuous T-cell receptor (TCR) engagement (11). Here electron microscopic studies are particularly valuable for their very high resolution, especially with the power of 3D tomography and highpressure freezing, which preserves cell structure more faithfully. Although a number of high-resolution electron microscopy studies of T cell-APC interactions have been reported (3,(12)(13)(14)(15), these involve studies of cytotoxic T or natural killer cells and their targets for only the first few minutes of CD4 + ...

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Section: Discussionmentioning

confidence: 99%

“…BM-DCs were prepared as described elsewhere (30). OT-1 primary cells were isolated from lymph nodes of transgenic mice, and conjugates were made as described previously (33).…”

Section: Methodsmentioning

confidence: 99%

CD4⁺T-cell synapses involve multiple distinct stages

Ueda

Morphew

McIntosh

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

114

109

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“…In these models, most signal amplification arises from a serial triggering mechanism that depends on low phosphatase activity. The assumption of low phosphatase activity is possibly satisfied in stages of TCR signaling after immunological synapse formation, but T cell killing does not require formation of a stable immunological synapse (Purbhoo et al, 2004).…”

Section: Model Formulationmentioning

confidence: 99%

“…Helper T cells, which express CD4, can be activated by as few as 10 agonist (stimulatory) pMHC present on an APC, and even the presence of a single agonist pMHC produces a measurable transient response (Irvine et al, 2002). Killer T cells, which express CD8, are more sensitive; only three pMHCs are required to induce T cell-mediated killing (Purbhoo et al, 2004). At the same time T cells ignore pMHCs with short binding lifetimes, which are typically much less than a second for self peptides.…”

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confidence: 99%

Stochastic effects and bistability in T cell receptor signaling

Lipniacki

Hat

Faeder

et al. 2008

Journal of Theoretical Biology

119

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The stochastic dynamics of T cell receptor (TCR) signaling are studied using a mathematical model intended to capture kinetic proofreading (sensitivity to ligand-receptor binding kinetics) and negative and positive feedback regulation mediated respectively by the phosphatase SHP1 and the MAP kinase ERK. The model incorporates protein-protein interactions involved in initiating TCR-mediated cellular responses and reproduces several experimental observations about the behavior of TCR signaling, including robust responses to as few as a handful of ligands (agonist peptide-MHC complexes on an antigen-presenting cell), distinct responses to ligands that bind TCR with different lifetimes, and antagonism. Analysis of the model indicates that TCR signaling dynamics are marked by significant stochastic fluctuations and bistability, which is caused by the competition between the positive and negative feedbacks. Stochastic fluctuations are such that single-cell trajectories differ qualitatively from the trajectory predicted in the deterministic approximation of the dynamics. Because of bistability, the average of single-cell trajectories differs markedly from the deterministic trajectory. Bistability combined with stochastic fluctuations allows for switch-like responses to signals, which may aid T cells in making committed cell-fate decisions.

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“…Cytolysis by CD8 cells seems to be an ultrasensitive response, not requiring the formation of a stable immunological synapse associated with full activation in CD4 cells (16). Some evidence suggests that class I MHC monomers are sufficient to induce signaling in T cells that have been "adhesion primed" by Ag nonspecific interactions on an APC or a surface coated with Abs to T cell surface molecules (17).…”

mentioning

confidence: 99%

CD8 T Cells, Like CD4 T Cells, Are Triggered by Multivalent Engagement of TCRs by MHC-Peptide Ligands but Not by Monovalent Engagement

Stone

Stern

2006

The Journal of Immunology

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T cell activation is initiated by recognition of antigenic peptide presented in complex with MHC molecules on the surface of APCs. The mechanism by which this recognition occurs is still unclear, and many models exist in the literature. CD4 T cells have been shown to respond to soluble oligomers of activating class II MHC-peptide complexes, but not to soluble monomers. In determining the reactivity of CD8 T cells to soluble activating class I MHC-peptide complexes, a complicating phenomenon had been observed whereby peptide from soluble complexes was loaded onto cell surface MHCs on the T cells and re-presented to other T cells, clouding the true valency requirement for activation. This study uses soluble allogeneic class I MHC-peptide monomers and oligomers to stimulate murine CD8 T cells without the possible complication of peptide re-presentation. The results show that MHC class I monomers bind to, but do not activate, CD8 T cells whether the cells are in solution or adhered to a surface. Monomeric MHC class I binding can antagonize the stimulation triggered by soluble oligomers, a phenomenon also observed for CD4 T cells. Dimeric engagement is necessary and sufficient to stimulate downstream activation processes including TCR down-regulation, Zap70 phosphorylation, and CD25 and CD69 up-regulation, even in T cells that do not express the MHC coreceptor CD8. Thus, the valency dependence of the response of CD8 T cells to soluble MHC-peptide reagents is the same as previously observed for CD4 T cells.

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T cell killing does not require the formation of a stable mature immunological synapse

Cited by 514 publications

References 36 publications

CD4⁺T-cell synapses involve multiple distinct stages

CD4⁺T-cell synapses involve multiple distinct stages

Stochastic effects and bistability in T cell receptor signaling

CD8 T Cells, Like CD4 T Cells, Are Triggered by Multivalent Engagement of TCRs by MHC-Peptide Ligands but Not by Monovalent Engagement

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T cell killing does not require the formation of a stable mature immunological synapse

Cited by 514 publications

References 36 publications

CD4+T-cell synapses involve multiple distinct stages

CD4+T-cell synapses involve multiple distinct stages

Stochastic effects and bistability in T cell receptor signaling

CD8 T Cells, Like CD4 T Cells, Are Triggered by Multivalent Engagement of TCRs by MHC-Peptide Ligands but Not by Monovalent Engagement

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CD4⁺T-cell synapses involve multiple distinct stages

CD4⁺T-cell synapses involve multiple distinct stages