THEMIS enhances TCR signaling and enables positive selection by selective inhibition of the phosphatase SHP-1

Choi, Seeyoung; Warzecha, Claude C.; Zvezdova, Ekaterina; Lee, Jan; Argenty, Jérémy; Lesourne, Renaud; Aravind, L.; Love, Paul E.

doi:10.1038/ni.3692

Cited by 74 publications

(150 citation statements)

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“…In Model 2, reducing the amount of SHP-1 in Themis −/− thymocytes should alleviate the block in positive selection. The results of this key experiment supported the mechanism proposed in Model 2 [23]. Thymocyte-specific deletion of Ptpn6, the gene encoding SHP-1, resulted in a dramatic rescue of positive selection demonstrated by increased SP thymocyte and T cell numbers in Themis −/− mice indicating that the Themis −/− defect is a result of increased SHP-1 activity [23].…”

Section: Examining the Evidence For Model 1 And Modelsupporting

confidence: 66%

“…The latter inhibitory mechanism, which represents a novel mode of biological PTP regulation, required the presence of Reactive Oxygen Species (ROS) at the time of TCR stimulation. Signaling defects, including reduced tyrosine phosphorylation of the protein tyrosine kinases LCK and ZAP-70, which are targets of SHP-1, were revealed in Themis −/− thymocytes following TCR stimulation in the presence but not in the absence of ROS (e.g., H 2 O 2 ) [23]. Collectively, these results suggested an alternative model for THEMIS function in thymocytes, referred to here as Model 2 (Fig.…”

Section: Two Models For Themis Functionmentioning

confidence: 99%

“…Despite their abundance, to date no CABIT containing proteins other than THEMIS, THEMIS2, THEMIS3, GAREM1 and GAREM2 and the Drosophila protein Serrano [60] have been extensively studied. The function of the THEMIS CABIT modules was recently determined (see text) [23]. …”

Section: The Themis Enigmamentioning

confidence: 99%

“…We discovered that the THEMIS CABIT modules bind directly to SHP-1 and inhibit SHP-1 PTP activity both in vitro and in vivo by blocking access to substrate and by promoting or sustaining oxidation of the SHP-1 catalytic cysteine [23], (Box 4). The latter inhibitory mechanism, which represents a novel mode of biological PTP regulation, required the presence of Reactive Oxygen Species (ROS) at the time of TCR stimulation.…”

Section: Two Models For Themis Functionmentioning

confidence: 99%

“…The proponents of Model 1 have proposed that positive regulation of both SHP-1 and the closely related but widely expressed SH2 PTP, SHP-2 by THEMIS could explain the milder phenotype of Ptpn6 −/− mice compared to Themis −/− mice if SHP-1 and SHP-2 are functionally redundant, and predicted that the phenotype of thymocytes lacking both SHP-1 and SHP-2 should phenocopy that of Themis −/− thymocytes [15]. However, this speculation is at odds with the recent finding that deletion of Ptpn6 rescues the developmental block in Themis −/− mice [23]. …”

Section: Examining the Evidence For Model 1 And Modelmentioning

confidence: 99%

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THEMIS: Two Models, Different Thresholds

Choi

Cornall

Lesourne

et al. 2017

Trends in Immunology

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THEMIS, a recently identified T-lineage restricted protein, is the founding member of a large metazoan protein family. Gene inactivation studies have revealed a critical requirement for THEMIS during thymocyte positive selection, implicating THEMIS in signaling downstream of the T cell antigen receptor (TCR); but the mechanistic underpinnings of THEMIS’ function have remained elusive. A previous model posited that THEMIS prevents thymocytes from inappropriately crossing the positive/negative selection threshold by dampening TCR signaling. However, new data suggest an alternative model where THEMIS enhances TCR signaling, enabling thymocytes to reach the threshold for positive selection avoiding death by neglect. We review the data supporting each model and conclude that the preponderance of evidence favors an enhancing function for THEMIS in TCR signaling.

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Section: Examining the Evidence For Model 1 And Modelsupporting

confidence: 66%

Section: Two Models For Themis Functionmentioning

confidence: 99%

Section: The Themis Enigmamentioning

confidence: 99%

Section: Two Models For Themis Functionmentioning

confidence: 99%

Section: Examining the Evidence For Model 1 And Modelmentioning

confidence: 99%

See 3 more Smart Citations

THEMIS: Two Models, Different Thresholds

Choi

Cornall

Lesourne

et al. 2017

Trends in Immunology

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Treatment with Exogenously Added Catalase Alters CD8 T Cell Memory Differentiation and Function

Aksoylar

Patsoukis

2022

Advanced Biology

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Cell‐based immunotherapy is a promising approach to cancer treatment. However, the metabolically hostile tumor microenvironment (TME) poses a major barrier to this therapeutic approach. Metabolic reprogramming may enhance T cell effector function and support longevity and persistence within the TME. Metabolic processes lead reactive oxygen species (ROS) production, which are mandatory mediators of signaling and immune cell functions, but detrimental when present in excess. Catalase (CAT) is an intracellular antioxidant enzyme that scavenges hydrogen peroxide (H2O2), a central ROS member with a plethora of biological effects. H2O2 is produced intracellularly and extracellularly, diffusing freely between the two compartments. In this study, it is found that scavenging extracellular H2O2 by CAT supplementation has a major impact on the cell redox state, decreased intracellular ROS, but enhanced activation and altered memory differentiation. Under in vitro chronic activation conditions, CAT treatment favors CD8 T cells with less exhausted phenotype, increased activation and memory markers, and high bioenergetic capacity. Under in vitro acute activation conditions, CAT treatment selectively prevents differentiation transition from the stem cell memory/naive (TSCM/TN)‐ to the central memory (TCM)‐like phenotype, while enhancing activation and polyfunctionality. The study highlights the critical role of H2O2 as a “hidden player” in T cell fitness and memory differentiation.

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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,...

show abstract

THEMIS enhances TCR signaling and enables positive selection by selective inhibition of the phosphatase SHP-1

Cited by 74 publications

References 50 publications

THEMIS: Two Models, Different Thresholds

THEMIS: Two Models, Different Thresholds

Treatment with Exogenously Added Catalase Alters CD8 T Cell Memory Differentiation and Function

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

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