First-in-class inhibitor of the T cell receptor for the treatment of autoimmune diseases

Borroto, Aldo; Reyes-Garau, Diana; Jiménez, M.; Carrasco, Esther; Moreno, Beatriz; Martinez‐Pasamar, Sara; Cortés, José R.; Perona, Almudena; Abia, David; Blanco, Soledad; Fuentes, Manuel; Arellano, Irene; Lobo, Juan M. García; Heidarieh, Haleh; Rueda, Javier; Esteve, Pilar; Cibrián, Danay; Martín, Pilar; Mendoza, Pilar; Prieto, Cristina; Calleja, E.; Órfão, Alberto; Fresno, Manuel; Sánchez-Madrid, Francisco; Alcamı́, Antonio; Bovolenta, Paola; Martı́n, Pilar; Villoslada, Pablo; Morreale, Antonio; Messeguer, Àngel; Alarcón, Balbino

doi:10.1126/scitranslmed.aaf2140

Cited by 45 publications

(62 citation statements)

References 51 publications

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“…Interestingly, the T‐cell response to a mouse pathogen acting as a strong high‐affinity peptide was normal after treatment with this inhibitor. Altogether, these results indicate that this synthetic inhibitor could be a candidate to be evaluated in clinical trials to treat various T‐cell‐mediated autoimmune diseases …”

Section: Nckmentioning

confidence: 86%

“…72 Hence, the requirement of Nck recruitment for T-cell activation only by low (and not by high) affinity antigens has raised the possibility for inhibition of the Nck-CD3 interaction as a target for treatment of autoimmune diseases caused by self-reactive T cells. Borroto et al 73 have chemically generated a lowmolecular-weight inhibitor targeting a non-canonical pocket within the Nck SH3.1 domain. As expected, this inhibitor prevented the binding of Nck to the TCR-CD3 complex.…”

Section: Nckmentioning

confidence: 99%

“…Altogether, these results indicate that this synthetic inhibitor could be a candidate to be evaluated in clinical trials to treat various T-cellmediated autoimmune diseases. 73 WASP WASP belongs to the WASP family of proteins consisting of WASP, N-WASP and WAVE/SCAR molecules. 74 Mutation of WASP or lack of WASP expression causes the Wiskott-Aldrich syndrome (WAS), which is characterized by thrombocytopenia, eczema, increased susceptibility to infection and increased risk to develop autoimmune disease.…”

Section: Nckmentioning

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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Section: Nckmentioning

confidence: 86%

Section: Nckmentioning

confidence: 99%

Section: Nckmentioning

confidence: 99%

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

2017

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“…Таким образом, патологии в структуре этого ком-плекса могут привести к дисфункции Т-к леток и развитию аутоиммунных заболеваний, таких как аутоиммунный сахарный диабет, системная красная волчанка и системная склеродермия [46]. Поскольку большинство аутоиммунных заболеваний считают-ся специфичными к антигену, то патология в струк-туре Т-клеточного рецептора, или нарушение его функциональной активности играют решающую роль в патогенезе заболеваний [13,89]. Каждый рецепторный комплекс имеет связи с вну-триклеточной системой ферментов, наиболее важ-ной являются тирозинкиназы, фосфотазы.…”

Section: роль рецепторов и ферментов в патогенезе миастении грависunclassified

Immunopathogenesis of Myasthenia Gravis (Review)

Gasymly¹

2018

Arhivʺ vnutr. med.

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“…15,16 Both isoforms consist of three SH3 domains (SH3Á1, SH3Á2 and SH3Á3) and one SH2 domain, and so potentially interact with proline-rich sequence (PRS)-bearing proteins and tyrosine phosphorylated proteins, respectively. Indeed, inhibiting the Nck-TCR interaction reduced actin polymerization, 24 showing that the Nck pool at the TCR significantly contributes to actin rearrangements. 20 Nck also functions as a linker for the recruitment and activation of other proteins in multiple intracellular signaling pathways.…”

Section: Introductionmentioning

confidence: 97%

Actin polymerization regulates recruitment of Nck to CD3εupon T‐cell receptor triggering

et al. 2019

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Following T-cell antigen receptor (TCR) engagement, rearrangement of the actin cytoskeleton supports intracellular signal transduction and T-cell activation. The non-catalytic region of the tyrosine kinase (Nck) molecule is an adapter protein implicated in TCR-induced actin polymerization. Further, Nck is recruited to the CD3e subunit of the TCR upon TCR triggering. Here we examine the role of actin polymerization in the recruitment of Nck to the TCR. To this end, Nck binding to CD3e was quantified in Jurkat cells using the proximity ligation assay. We show that inhibition of actin polymerization using cytochalasin D delayed the recruitment of Nck1 to the TCR upon TCR triggering. Interestingly, CD3e phosphorylation was also delayed. These findings suggest that actin polymerization promotes the recruitment of Nck to the TCR, enhancing downstream signaling, such as phosphorylation of CD3e.Abbreviations: CD3e, cluster of differentiation 3e; CREB, cyclic AMP-response element binding protein; CytD, cytochalasin D; Erk, extracellular signal-regulated kinase; F-actin, filamentous actin; LAT, linker of activated T cells; Lck, lymphocyte-specific protein tyrosine kinase; MHC, major histocompatibility complex; Nck, non-catalytic region of tyrosine kinase ; PLA, proximity ligation assay; PRS, proline-rich sequence; SH domain, Src homology domain; SLP-76, SH domain containing leukocyte protein of 76 000 MW; TCR, T-cell receptor; WAsP, Wiskott--Aldrich syndrome protein; ZAP70, f chain-associated protein kinase of 70 000 MW ª

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First-in-class inhibitor of the T cell receptor for the treatment of autoimmune diseases

Abstract: A novel inhibitor of interactions between signaling proteins in T cells demonstrates promising preventive and therapeutic effects in several models of autoimmune disease.

Cited by 45 publications

References 51 publications

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

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

Immunopathogenesis of Myasthenia Gravis (Review)

Actin polymerization regulates recruitment of Nck to CD3εupon T‐cell receptor triggering

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