A cycle of Zap70 kinase activation and release from the TCR amplifies and disperses antigenic stimuli

Katz, Zachary; Novotná, Lucie; Blount, Amy L.; Lillemeier, Björn F.

doi:10.1038/ni.3631

Cited by 78 publications

(109 citation statements)

References 54 publications

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“…The CD3ε immunoreceptor tyrosine‐based activation motif (ITAM), however, was already found phosphorylated in ex vivo isolated, non‐stimulated Treg cells. Hence it is fair to speculate that the signal amplification mechanism involving the dissociation of ZAP70 from the TCR complex, as very recently described for Tconv cells , is already induced in non‐stimulated Treg cells. This would support ZAP70 function in inside‐out signalling and adhesion of Treg cells, which did not require its kinase activity .…”

Section: Discussionmentioning

confidence: 72%

TCR signalling network organization at the immunological synapses of murine regulatory T cells

et al. 2017

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Regulatory T (Treg) cells require T-cell receptor (TCR) signalling to exert their immunosuppressive activity, but the precise organization of the TCR signalling network compared to conventional T (Tconv) cells remains elusive. By using accurate mass spectrometry and multi-epitope ligand cartography (MELC) we characterized TCR signalling and recruitment of TCR signalling components to the immunological synapse (IS) in www.eji-journal.euThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. 2Marco van Ham et al. Eur. J. Immunol. 2017. 0: 1-16 in Treg cells, thereby, seems to be differentially organized as in Tconv cells: Treg cells show reduced Ca 2+ flux and ERK1/2 phosphorylation upon TCR stimulation [6][7][8], and downstream signalling molecules such as Lck, LAT and PLCγ1 are essential for Treg cell suppressive capacity [9,10]. In this line, a novel TCRmediated ADAP/integrin-independent PLCγ1 activation pathway was described to be required for suppression of Tconv cells by Treg cells [11]. Furthermore, Treg cells exhibit reduced S473 phosphorylation of Akt which seems a prerequisite for suppression [12]. Although the enzymatic activity of the tyrosine kinase ZAP70 seems to be dispensable for the suppressive phenotype of Foxp3 + Treg cells [13], a single mutation within the SH2-domain of ZAP70 leads to impaired suppressive activities, which indicated its importance at the immunological synapse (IS) [14]. Finally, it has only recently been recognized that the recruitment of TCR signalling components into the IS is differentially organized in Treg cells and Tconv cells. The protein kinase PKCθ is recruited to the IS in Tconv cells, in Treg cells, however, this kinase was found to be sequestered away from the IS, but still of importance to control suppression [15]. The spatial recruitment of signalling components during IS formation critically depends on cytoskeleton dynamics, which in turn is controlled by TCR activation and subsequent phosphorylation of proteins regulating cytoskeleton reorganization [5]. As part of these processes the microtubule-organizing centre (MTOC) is rapidly translocated in proximity to the IS. MTOC repositioning depends on LAT, ZAP70 and SLP76 [16] and is regulated by a cascade of distinct isoforms of the family of novel protein kinase C (nPKC) [17]. The MTOC serves as a platform to coordinate molecular movements from and to the IS through the support of microtubule (MT) motors [18]. For instance, TCR microclusters move along MTs towards the centre of the IS in a dynein-dependent manner [19], and hindrance of MTOC polarization, molecular transport and cytoskeleton dynamics prevent proper propagation of TCR signals [20].It is now tempting to speculate that the localization of signalling modules within the IS may be instrumental for the formation of a Treg cell-specific IS and the suppressive phenotype of Treg cells. At this moment, however,...

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Section: Discussionmentioning

confidence: 72%

TCR signalling network organization at the immunological synapses of murine regulatory T cells

et al. 2017

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“…When bound to the TCR, ZAP‐70 can be activated to phosphorylate downstream targets that ultimately lead to T cell activation. Therefore, a single TCR/pMHC‐binding event can potentially be translated into the activation of multiple ZAP‐70 molecules . This signaling may also be sustained beyond pMHC binding because it has been suggested that, upon internalization, TCRs may continue to signal within the T cell .…”

Section: Mechanisms Of T‐cell Sensitivity To Antigenmentioning

confidence: 99%

Molecular mechanisms of T cell sensitivity to antigen

Siller-Farfán

Dushek

2018

Immunological Reviews

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T cells initiate and regulate adaptive immune responses that can clear infections. To do this, they use their T cell receptors (TCRs) to continually scan the surfaces of other cells for cognate peptide antigens presented on major histocompatibility complexes (pMHCs). Experimental work has established that as few 1-10 pMHCs are sufficient to activate T cells. This sensitivity is remarkable in light of a number of factors, including the observation that the TCR and pMHC are short molecules relative to highly abundant long surface molecules, such as CD45, that can hinder initial binding, and moreover, the TCR/pMHC interaction is of weak affinity with solution lifetimes of approximately 1 second. Here, we review experimental and mathematical work that has contributed to uncovering molecular mechanisms of T cell sensitivity. We organize the mechanisms by where they act in the pathway to activate T cells, namely mechanisms that (a) promote TCR/pMHC binding, (b) induce rapid TCR signaling, and (c) amplify TCR signaling. We discuss work showing that high sensitivity reduces antigen specificity unless molecular feedbacks are invoked. We conclude by summarizing a number of open questions.

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“…By comparing the different ITAMs among the CD3 subunits (CD3 ζ , CD3 δ , CD3 ε and CD3 γ ), it is likely that ZAP‐70 preferentially binds to fully phosphorylated CD3 ζ . Recently, a ‘catch‐and‐release’ model for ZAP‐70 activation has been proposed by Katz et al . After recruitment of ZAP‐70 to the phosphorylated TCR–CD3 complexes and ZAP‐70 phosphorylation by Lck, activated ZAP‐70 is released from the TCR–CD3 complexes into the plane of the plasma membrane.…”

Section: Zap‐70mentioning

confidence: 99%

“…Consequently, empty phospho‐TCR–CD3 complexes allow the recruitment of additional ZAP‐70 molecules to the TCR–CD3 for activation of additional ZAP‐70. The released ZAP‐70 translocates within the membrane into adjacent protein islands to mediate phosphorylation of its substrates including the linker for the activation of T cells (LAT) and the SH2‐domain‐containing leucocyte protein of 76 000 MW (SLP‐76) . Phosphorylated LAT and SLP‐76 adaptor proteins have various interacting partners such as the phospholipase C‐γ1, which is recruited to these two proteins to form the LAT/SLP‐76 signalosome .…”

Section: Zap‐70mentioning

confidence: 99%

“…[49][50][51] By comparing the different ITAMs among the CD3 subunits (CD3f, CD3d, CD3e and CD3c), it is likely that ZAP-70 preferentially binds to fully phosphorylated CD3f. 9 Recently, a 'catch-and-release' model for ZAP-70 activation has been proposed by Katz et al 55 After recruitment of ZAP-70 to the phosphorylated TCR-CD3 complexes and ZAP-70 phosphorylation by Lck, activated ZAP-70 is released from the TCR-CD3 complexes into the plane of the plasma membrane. The association of ZAP-70 with the membrane might be mediated by the binding of the SH2 domains to lipids or of phosphotyrosines to other membrane-associated proteins.…”

Section: Zap-70mentioning

confidence: 99%

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Selected signalling proteins recruited to the T‐cell receptor–CD3 complex

2017

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SummaryThe T-cell receptor (TCR)-CD3 complex, expressed on T cells, determines the outcome of a T-cell response. It consists of the TCR-ab heterodimer and the non-covalently associated signalling dimers of CD3ec, CD3ed and CD3ff. TCR-ab binds specifically to a cognate peptide antigen bound to an MHC molecule, whereas the CD3 subunits transmit the signal into the cytosol to activate signalling events. Recruitment of proteins to specialized localizations is one mechanism to regulate activation and termination of signalling. In the last 25 years a large number of signalling molecules recruited to the TCR-CD3 complex upon antigen binding to TCR-ab have been described. Here, we review knowledge about five of those interaction partners: Lck, ZAP-70, Nck, WASP and Numb. Some of these proteins have been targeted in the development of immunomodulatory drugs aiming to treat patients with autoimmune diseases and organ transplants.

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A cycle of Zap70 kinase activation and release from the TCR amplifies and disperses antigenic stimuli

Cited by 78 publications

References 54 publications

TCR signalling network organization at the immunological synapses of murine regulatory T cells

TCR signalling network organization at the immunological synapses of murine regulatory T cells

Molecular mechanisms of T cell sensitivity to antigen

Selected signalling proteins recruited to the T‐cell receptor–CD3 complex

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