Full Activation of the T Cell Receptor Requires Both Clustering and Conformational Changes at CD3

Minguet, Susana; Swamy, Mahima; Alarcón, Balbino; Luescher, Immanuel F.; Schamel, Wolfgang W. A.

doi:10.1016/j.immuni.2006.10.019

Cited by 235 publications

(272 citation statements)

References 53 publications

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“…However, it might be less relevant with regard to T cells, as long as the spacing of individual cognate pMHC molecules does not exceed a critical distance. In vitro studies with artificial TCR ligands are compatible with the existence of such spacing constraints on T cell activation (38).…”

Section: Discussionmentioning

confidence: 85%

Cognate Peptide–MHC Complexes Are Expressed as Tightly Apposed Nanoclusters in Virus-Infected Cells To Allow TCR Crosslinking

Ferez

Castro

Alarcón

et al. 2014

The Journal of Immunology

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Antigenic T cell stimulation requires interaction between the TCR of the T cell and cognate peptide–MHC molecules presented by the APC. Although studies with TCR-specific Abs and soluble peptide–MHC ligands have shown that the TCR needs to be crosslinked by two or more ligands to induce T cell stimulation, it is not understood how several MHC molecules loaded with the cognate antigenic peptide can produce crosslinking under physiological conditions. We show at the molecular level that large clusters of cognate peptide–MHC are formed at the surface of murine professional and nonprofessional APCs upon virus infection and that these clusters impinge on the stimulatory capacity of the APC. These clusters are formed by tight apposition of cognate peptide–MHC complexes in a configuration that is compatible with simultaneous engagement of two or more TCRs. This suggests that physiological expression of Ag allows formation of multivalent ligands for the TCR that permit TCR crosslinking and T cell activation.

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Section: Discussionmentioning

confidence: 85%

Cognate Peptide–MHC Complexes Are Expressed as Tightly Apposed Nanoclusters in Virus-Infected Cells To Allow TCR Crosslinking

Ferez

Castro

Alarcón

et al. 2014

The Journal of Immunology

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“…Clearly, leaky and dead cells cannot maintain ion gradients, precluding Ca 2+ --signalling. Despite the cells being leaky, the aggregation of GM1--domains may have been sufficient to colocalise the molecules necessary for pTyr when stimulated by an antibody inducing a favourable conformational change in the TCR [44]. This is further supported by the finding that pTyr is maintained long after cell death [11].…”

Section: Discussionmentioning

confidence: 87%

Limited cholesterol depletion causes aggregation of plasma membrane lipid rafts inducing T cell activation

Mahammad

Dinić

Adler

et al. 2010

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Acute cholesterol depletion is generally associated with decreased or abolished T cell signalling but it can also cause T cell activation. This anomaly has been addressed in Jurkat T cells using progressive cholesterol depletion with methyl--beta--cyclodextrin (MBCD). At depletion levels higher than 50% there is substantial cell death, which explains reports of signalling inhibition. At 10--20% depletion levels, tyrosine phosphorylation is increased, ERK is activated and there is a small increase in cytoplasmic Ca 2+ . Peripheral actin polymerisation is also triggered by limited cholesterol depletion. Strikingly, the lipid raft marker GM1 aggregates upon cholesterol depletion and these aggregated domains concentrate the signalling proteins Lck and LAT, whereas the opposite is true for the non lipid raft marker the transferrin receptor. Using PP2, an inhibitor of Src family kinase activation, it is demonstrated that the lipid raft aggregation occurs independently of and thus upstream of the signalling response. Upon cholesterol depletion there is an increase in overall plasma membrane order, indicative of more liquid ordered domains forming at the expense of liquid disordered domains. That cholesterol depletion and not unspecific effects of MBCD was behind the reported results was confirmed by performing all experiments with MBCD--cholesterol, when no net cholesterol extraction took place. We conclude that non--lethal cholesterol depletion causes the aggregation of lipid rafts which then induces T cell signalling.

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“…Bi-or multivalent Ag binding to TCRab induces conformational changes at CD3 and leads to CD3 and z phosphorylation (11). Consequently, the kinase ZAP70 is recruited and activated (12), thereby phosphorylating the downstream adaptor molecules LAT and SLP76.…”

mentioning

confidence: 99%

Kidins220/ARMS Associates with B-Raf and the TCR, Promoting Sustained Erk Signaling in T Cells

Deswal

Meyer

Fiala

et al. 2013

The Journal of Immunology

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The activation kinetics of MAPK Erk are critical for T cell development and activation. In particular, sustained Erk signaling is required for T cell activation and effector functions, such as IL-2 production. Although Raf-1 triggers transient Erk activation, B-Raf is implicated in sustained Erk signaling after TCR stimulation. In this study, we show that B-Raf is dephosphorylated on its inhibitory serine 365 upon TCR triggering. However, it is unknown how B-Raf activation is coupled to the TCR. Using mass spectrometry, we identified protein kinase D–interacting substrate of 220 kDa (Kidins220)/ankyrin repeat-rich membrane spanning protein, mammalian target of rapamycin, Rictor, Dock2, and GM130 as novel B-Raf interaction partners. We focused on Kidins220, a protein that has been studied in neuronal cells and found that it associated with the pre-TCR, αβTCR, and γδTCR. Upon prolonged TCR stimulation, the Kidins220–TCR interaction was reduced, as demonstrated by immunoprecipitation and proximity ligation assays. We show that Kidins220 is required for TCR-induced sustained, but not transient, Erk activation. Consequently, induction of the immediate early gene products and transcription factors c-Fos and Erg-1 was blocked, and upregulation of the activation markers CD69, IL-2, and IFN-γ was reduced. Further, Kidins220 was required for optimal calcium signaling. In conclusion, we describe Kidins220 as a novel TCR-interacting protein that couples B-Raf to the TCR. Kidins220 is mandatory for sustained Erk signaling; thus, it is crucial for TCR-mediated T cell activation.

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Full Activation of the T Cell Receptor Requires Both Clustering and Conformational Changes at CD3

Cited by 235 publications

References 53 publications

Cognate Peptide–MHC Complexes Are Expressed as Tightly Apposed Nanoclusters in Virus-Infected Cells To Allow TCR Crosslinking

Cognate Peptide–MHC Complexes Are Expressed as Tightly Apposed Nanoclusters in Virus-Infected Cells To Allow TCR Crosslinking

Limited cholesterol depletion causes aggregation of plasma membrane lipid rafts inducing T cell activation

Kidins220/ARMS Associates with B-Raf and the TCR, Promoting Sustained Erk Signaling in T Cells

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