The Balance between T Cell Receptor Signaling and Degradation at the Center of the Immunological Synapse Is Determined by Antigen Quality

Čemerski, Sašo; Das, Jayajit; Giurisato, Emanuele; Markiewicz, Mary A.; Allen, Paul M.; Chakraborty, Arup K.; Shaw, Andréy S.

doi:10.1016/j.immuni.2008.06.014

Cited by 127 publications

(132 citation statements)

References 45 publications

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“…Microclusters play a predominant role in the generation of sustained signals. Current models also indicate that cluster centralization plays an important role in signal termination and that the cSMAC is a site both for TCR down-regulation yet also for amplification of weak signals (Lee et al 2003;Mossman et al 2005;Varma et al 2006;Balagopalan et al 2007;Cemerski et al 2008;Nguyen et al 2008). A recent study using a photoactivatable agonist in a lipid bilayer system has provided even greater precision in the temporal resolution of these events and demonstrated that adapters are recruited to microclusters within four seconds (Huse et al 2007).…”

Section: Lat Microclusters: Sites Of Nucleation Of Signaling Complexesmentioning

confidence: 99%

The LAT Story: A Tale of Cooperativity, Coordination, and Choreography

Balagopalan¹,

Coussens²,

Sherman³

et al. 2010

Cold Spring Harbor Perspectives in Biology

153

184

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The adapter molecule LAT is a nucleating site for multiprotein signaling complexes that are vital for the function and differentiation of T cells. Extensive investigation of LAT in multiple experimental systems has led to an integrated understanding of the formation, composition, regulation, dynamic movement, and function of LAT-nucleated signaling complexes. This review discusses interactions of signaling molecules that bind directly or indirectly to LAT and the role of cooperativity in stabilizing LAT-nucleated signaling complexes. In addition, it focuses on how imaging studies visualize signaling assemblies as signaling clusters and demonstrate their dynamic nature and cellular fate. Finally, this review explores the function of LAT based on the interpretation of mouse models using various LAT mutants.

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Section: Lat Microclusters: Sites Of Nucleation Of Signaling Complexesmentioning

confidence: 99%

The LAT Story: A Tale of Cooperativity, Coordination, and Choreography

Balagopalan¹,

Coussens²,

Sherman³

et al. 2010

Cold Spring Harbor Perspectives in Biology

153

184

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“…The protein patterns are not static on the cell surface 18,19 . Instead, they evolve on the timescale of signalling, usually over the course of minutes, and can change depending on the cell signalling state 15,16 . Here, we highlight recent evidence suggesting that the spatial organization of proteins at cell-cell interfaces may be a widespread regulatory mechanism of intercellular signal transduction.…”

Section: Hhmi Author Manuscriptmentioning

confidence: 99%

“…For example, this can result in location-specific signalling of identical receptors. Recent evidence suggests that the spatial organization of the immunological synapse has an active role in regulating the signalling state of individual molecular components, and thus can alter long-term cell activation [15][16][17] . Various different spatial arrangements can occur between different types of immune cells and their respective targets, correlating with different functions 8,13 .…”

mentioning

confidence: 99%

Spatial organization and signal transduction at intercellular junctions

Manz

Groves

2010

Nat Rev Mol Cell Biol

122

114

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The coordinated organization of cell membrane receptors into diverse micrometre-scale spatial patterns is emerging as an important theme of intercellular signalling, as exemplified by immunological synapses. Key characteristics of these patterns are that they transcend direct protein-protein interactions, emerge transiently and modulate signal transduction. Such cooperativity over multiple length scales presents new and intriguing challenges for the study and ultimate understanding of cellular signalling. As a result, new experimental strategies have emerged to manipulate the spatial organization of molecules inside living cells. The resulting spatial mutations yield insights into the interweaving of the spatial, mechanical and chemical aspects of intercellular signalling.Cell-to-cell communication is mediated by various methods. Endocrine signals are secreted and reach distant target cells, paracrine signals are secreted and reach targets in the vicinity, and autocrine signals are secreted and received by the same cell. By contrast, in juxtacrine signalling, surfaces of interacting cells come into direct contact and receptor-ligand recognition at this interface triggers intracellular signalling. Cell-cell interactions involve multiple adhesion and signalling molecules, the collective behaviour of which regulates signal transduction 1 . Also intrinsic to juxtacrine signalling configurations are large physical constraints on molecular movement and assembly. Genetic and biochemical approaches have been invaluable in identifying the molecular components of signal transduction pathways in juxtacrine signalling and in characterizing the biochemical interactions among them. Despite this wealth of information, in many cases it remains impossible to describe the behaviour of a signalling system in terms of the individual molecular properties of its components. Protein-protein inter actions and the formation of molecular clusters are widely implicated in signal transduction and contribute to a first level of cooperativity [2][3][4] . Recently, the coordinated organization of cell membrane receptors into micrometre-scale patterns has emerged as a broadly important theme of intercellular signalling 1,[5][6][7][8][9] .A paradigm for the interplay of spatial patterns and signal transduction is the junction between T cells and their target cells, termed the immunological synapse [8][9][10][11][12][13] . Spatial HHMI Author Manuscript HHMI Author Manuscript HHMI Author Manuscriptpatterns of proteins at the cell-cell interface develop as hundreds of receptors recognize their cognate ligands on the apposed cell membrane. Multiple signalling and adhesion molecules also become organized into distinctive spatial patterns at the interface between the two cells 8,9,13,14 (FIG. 1). The patterns create long-range interactions and seem to have specific purposes in signal transduction 8,9 . They host the local enrichment or depletion of key signalling components, which can bias biochemical cascades towards different functional o...

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“…41 Experiments were also conducted to determine the ability of specific APLs to induce positive selection of CD4 lineage transgenic T cells. For a pigeon cytochrome C (PCC) [43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58] peptidespecific TCR, injections of agonist peptide alone or a mixture of antagonist and agonist peptides were given to Ii, H-2M double KO mice. 42 When injected alone, agonist peptide presumably repopulated MHC molecules in the thymus and supported positive selection of the transgenic T cells that continued for up to 2 weeks.…”

Section: Repertoires For Positive Selection Of Mhc2 Restricted Tcrsmentioning

confidence: 99%

“…53,54 Signaling molecules and kinases, such as Lck, Zap-70, LAT, SLP-76, 50,52,54 and Grb2, 55 are localized to TCR microclusters, which translocate from the periphery of the synapse to the center in an actin dependent manner where signaling is terminated, 51 although the precise function of the cSMAC remains unresolved. 56 TCR microclusters form continuously, thus providing a signaling microclusters containing TCR, CD4 and CD8 that may recognize many self-peptide-MHC complexes. This promiscuous signal transduction would be amplified by the reduction in phosphatase activity in DP thymocytes described previously.…”

Section: Tcr Microclustersmentioning

confidence: 99%