T Cell Receptor Signaling Precedes Immunological Synapse Formation

Lee, Kyeong-Hee; Holdorf, Amy D.; Dustin, Michael L.; Chan, Andrew C.; Allen, Paul M.; Shaw, Andréy S.

doi:10.1126/science.1067710

Cited by 633 publications

(589 citation statements)

References 27 publications

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“…Whether the previously reported loss of lipid domain association of CD4 in Th2 cells might thus represent a secondary effect of this quantitative change and the alteration in signaling leads to this, will require additional investigation. Our description of very early acting SHP-1-dependent negative feedback in controlling the TCR signal quality and duration [19], along with the evidence from this and other laboratories that the early phosphorylation of TCR-associated components precedes synapse formation [22], is consistent with the view that these previously reported aspects of CD4 behavior may be a downstream consequence rather than a primary cause of the Th2 pattern of signaling.…”

Section: Discussionsupporting

confidence: 89%

Decreased CD4 expression by polarized T helper 2 cells contributes to suboptimal TCR-induced phosphorylation and reduced Ca2+ signaling

et al. 2005

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Polarized Th1 and Th2 cells expressing the same TCR produce distinct biochemical responses to ligand engagement. Compared to Th1 cells, Th2 cells show altered substrate tyrosine phosphorylation and a diminished or transient Ca 2+ response. Here we demonstrate that agonist stimulation of Th1 cells leads to the predominant appearance of fully phosphorylated (p23) TCR f, substantial phosphorylation of zetaassociated protein 70 (ZAP-70), and strong elevation of intracellular Ca 2+ , whereas agonist stimulation of Th2 cells expressing an identical TCR results in an elevated p21:p23 TCR f ratio, little or no detectable ZAP-70 phosphorylation, and a more limited elevation in intracellular Ca 2+ . Th2 cells consistently had twofold lower surface CD4 expression as compared to Th1 cells with the same TCR. When CD4 levels in Th2 cells were raised to Th1 levels using retroviral gene transfer, the transduced cells showed greater generation of p23 phospho-f, measurable phosphorylation of ZAP-70, and increased Ca 2+ responses. These findings suggest that the apparent qualitative differences in TCR signaling characterizing Th1 versus Th2 cells are largely the result of modest quantitative variation in CD4 expression, with decreased CD4 expression playing a significant role in attenuating the proximal signaling responsiveness of Th2 cells to TCR ligands.Supporting information for this article is available at http://www.wileyvch.de/contents/jc_2040/2005/26064_s.pdf IntroductionWhile it is an oversimplification of in vivo physiology, the Th1-Th2 model is a convenient and generally applicable paradigm for naive CD4 + T cell differentiation [1,2]. The set of effector cytokines produced by an antigenactivated CD4 + T cell is largely determined by the particular combination of T cell receptor (TCR), cytokine, and costimulatory signals received by the naive T cell. In particular, T cells expressing the same The altered downstream phosphorylation seen in Th2 cells resembles that reported by this laboratory for Th1 cells in which CD4-MHC class II interactions are disrupted [14]. Therefore, we undertook a re-examination of the status of the CD4 molecule in polarized Th2 cells. Here we report that such cells consistently show a lower surface level of CD4 expression than Th1 cells derived from the same precursor pool. This lower CD4 expression could be linked to the altered signaling pattern of the Th2 cells through experiments showing a switch to a more Th1-like pattern of tyrosine phosphorylation and Ca 2+ signaling following enhancement of CD4 expression using a retroviral vector. These data provide evidence that a modest quantitative change in expression of a surface receptor can have qualitative effects on signaling in differentiated T cells and that decreased CD4 expression plays a significant role in controlling the antigen responsiveness of polarized Th2 cells. Results Differential TCR down-modulation in response to agonist by Th1 vs. Th2 cells expressing identical TCRTo examine in a controlled fashion the origin of the differences...

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Section: Discussionsupporting

confidence: 89%

Decreased CD4 expression by polarized T helper 2 cells contributes to suboptimal TCR-induced phosphorylation and reduced Ca2+ signaling

et al. 2005

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“…For example, it has been suggested that the immunological synapse that forms between the T cell and the Ag-presenting cell facilitates T cell receptor signaling by clustering the receptor and other signaling molecules [20]. Recent studies indicated, however, that initiation of T cell receptor-mediated signaling could occur early and could largely precede the formation of the mature immunological synapse [21,22]. Furthermore, recent in vitro and in silico experiments suggest that the immunological synapse acts as a type of adaptive controller that boosts both strong receptor triggering and increased TCR degradation [23].…”

Section: Discussionmentioning

confidence: 99%

“…In control cells exposed to 125 I-IgE instead of anti-Fc 4 RI Ab, most of the 125 I-IgEFc 4 RI complexes (94±8%; mean ± SD, n=4) were found in the high-density fractions of the sucrose gradient (fractions [11][12][13][14][15][16][17][18][19][20][21][22], and only a small portion (5.8±2.2%) was found in the low-density fractions (fractions 1-10; Fig. 1E, F).…”

Section: Differences In Degranulation Calcium Response and Drm Recrumentioning

confidence: 99%

Signaling assemblies formed in mast cells activated via Fcϵ receptor I dimers

et al. 2004

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Although aggregation of the Fc 4 receptor I (Fc 4 RI) is necessary for Ag-mediated mast cell triggering, the relationship between the extent of the Fc 4 RI aggregation and subsequent biochemical and topographical events is incompletely understood. In this study, we analyzed the activation events induced by Fc 4 RI dimers, elicited by binding of anti-Fc 4 RI mAb to rat basophilic leukemia cells. We found that, in contrast to extensively aggregated Fc 4 RI, receptor dimers (1) induced a less extensive association of Fc 4 RI with detergent-resistant membranes, (2) delayed the tyrosine phosphorylation and membrane recruitment of several signaling molecules, (3) triggered a slower but more sustained increase in concentration of free cytoplasmic calcium, (4) induced degranulation which was not inhibited at higher concentrations of the cross-linking mAb, and (5) failed to produce clusters of Fc 4 RI, Syk kinase and Grb2 adapter in osmiophilic membranes, as detected by immunogold electron microscopy on membrane sheets. Despite striking differences in the topography of Fc 4 RI dimers and multimers, biochemical differences were less pronounced. The combined data suggest that Fc 4 RI-activated mast cells propagate signals from small signaling domains formed around dimerized/oligomerized Fc 4 RI; formation of large Fc 4 RI aggregates in osmiophilic membranes seems to promote both strong receptor triggering and rapid termination of the signaling responses.

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“…The model has been formulated to capture early membrane-proximal events in TCR signaling. Because the model omits later events, such as immunological synapse formation (Bromey et al 2001;Lee et al 2002) and TCR mediated internalization of peptide-MHC (Huang et al 1999), the physiological relevance of model predictions becomes more uncertain as the time required to reach a steady state increases. However, steady-state results do reveal the long-time behavior of the system in isolation from downstream events, and they provide a starting point for future studies of the effects of these downstream events.…”

Section: Bistability Deterministic Versus Stochastic Trajectoriesmentioning

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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T Cell Receptor Signaling Precedes Immunological Synapse Formation

Cited by 633 publications

References 27 publications

Decreased CD4 expression by polarized T helper 2 cells contributes to suboptimal TCR-induced phosphorylation and reduced Ca2+ signaling

Decreased CD4 expression by polarized T helper 2 cells contributes to suboptimal TCR-induced phosphorylation and reduced Ca2+ signaling

Signaling assemblies formed in mast cells activated via Fcϵ receptor I dimers

Stochastic effects and bistability in T cell receptor signaling

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