Tespa1 regulates T cell receptor-induced calcium signals by recruiting inositol 1,4,5-trisphosphate receptors

Liang, Jingjing; Lyu, Jun; Zhao, Meng; Li, Dan; Zheng, Mingzhu; Yan, Fang; Zhao, Fangzhu; Lou, Jun; Guo, Chao; Wang, Lie; Wang, Di; Liu, Wanli; Lu, Linrong

doi:10.1038/ncomms15732

Cited by 31 publications

(22 citation statements)

References 26 publications

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“…Tespa1 plays an important role in T cell development and negatively regulates Fc εR1-mediated mast cell activation and allergic reactions [13,14]. The regulation of Tespa1 on mast cells is related to the negative regulation of the IL-4/STAT6 signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

“…The preferential assembly of the LAT2 promoted by Tespa1 might serve as a reservoir to regulate the signal strength of LAT1. IP3R1 (inositol 1,4,5-trisphosphate receptor type 1) can be recruited into the LAT2 complex by Tespa1 and then dephosphorylated to inhibit the activity [13,14]. However, the role of Tespa1 in the IL-4/STAT6 signaling pathway, an important pathway for mast cell function and asthma pathogenesis, remains unclear.…”

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confidence: 99%

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Tespa1 plays a role in the modulation of airway hyperreactivity through the IL-4/STAT6 pathway

Yang

Wang

et al. 2020

Preprint

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Background: Thymocyte-expressed, positive selection-associated 1 (Tespa1) is a critical signaling molecule in thymocyte development. This study aimed to investigate the regulatory effect of Tespa1 on mast cells in the pathogenesis of asthma and its relationship with the interleukin (IL)-4 /signal transducers and activators of transcription 6 (STAT6) signaling pathway.Methods: Tespa1 mRNA expression analysis and IgE levels were carried out using the induced sputum of 33 adults with stable asthma and 36 healthy controls. Tespa1- knockout mice ( Tespa1 -/- , KO) and C57BL/6 background (wild-type, WT) mice were sensitized and treated with ovalbumin (OVA) to establish an asthma model. Pathological changes, number and activity of mast cells, and changes in activation of the IL-4 /STAT6 pathway in lung tissue were detected. The changes of tryptase expression and STAT6 activation after mast cell gene knockout were analyzed in vitro . The changes of enzyme activation and STAT6 activation after mast cell gene knockout were analyzed in vitro . The association between the Tespa1 and p-STAT6 was analyzed by co-immunoprecipitation method.Results: Compared with the healthy controls, Tespa1 expression was decreased, and IgE levels were elevated in the sputum of asthmatic patients. Animal experiments showed that Tespa1 -/- mice exhibited more severe inflammation, higher quantity of goblet cells and mast cells in the bronchium, and greater activity of mast cell tryptase, which is induced by ovalbumin, than WT mice. And IL-4, IL-13, phospho-Janus kinase 1, and p-STAT6 expressions presented a higher increase in the Tespa1 -/- mouse model than in the WT mouse model. Further in vitro studies confirmed that IL-4 could more significantly promote tryptase and p-STAT6 activities in Tespa1 -/- mast cells than their WT counterparts. Correlation analysis results showed a negative correlation between Tespa1 and p-STAT6. Co-immunoprecipitation results demonstrated an association between Tespa1 and p-STAT6.Conclusions: Altogether, our results indicate that Tespa1 can negatively regulate mast cell activity, and this event is related to the mast cell IL-4/STAT6 signaling pathway and could be therapeutically exploited to treat asthma attacks.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Tespa1 plays a role in the modulation of airway hyperreactivity through the IL-4/STAT6 pathway

Yang

Wang

et al. 2020

Preprint

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“…Tespa1 plays an important role in T cell development and negatively regulates Fc εR1-mediated mast cell activation and allergic reactions [13,30]. The regulation of Tespa1 on mast cells is related to the negative regulation of the IL-4/STAT6 signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Tespa1 Negatively Modulates Asthmatic Attack Is Associated with IL-4/STAT-6 Pathway of Mast Cell

Yang

Wang

et al. 2019

SSRN Journal

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Background Thymocyte-expressed, positive selection-associated 1 (Tespa1) is a critical signaling molecule in thymocyte development. This study aimed to investigate the regulatory effect of Tespa1 on mast cells in the pathogenesis of asthma and its relationship with the interleukin (IL)-4 /signal transducers and activators of transcription 6 (STAT6) signaling pathway. Methods Tespa1 mRNA expression analysis and IgE levels were carried out using the induced sputum of 33 adults with stable asthma and 36 healthy controls. Tespa1-knockout mice (Tespa1-/-, KO) and C57BL/6 background (wild-type, WT) mice were sensitized and treated with ovalbumin (OVA) to establish an asthma model. Pathological changes, number and activity of mast cells, and changes in activity of the IL-4 /STAT-6 pathway in lung tissue were detected. The changes of enzyme activity and STAT6 activity after mast cell gene knockout were analyzed in vitro. The changes of enzyme activity and STAT6 activity after mast cell gene knockout were analyzed in vitro. The association between the Tespa1 and P-STAT6 was analyzed by immunoprecipitation method. Results Compared with the healthy controls, Tespa1 expression was decreased, and IgE levels were elevated in the sputum of asthmatic patients. Animal experiments showed that Tespa1-/-mice exhibited more severe in ammation, higher quantity of goblet cells and mast cells in the bronchium, and greater activity of mast cell tryptase, which is induced by ovalbumin, than WT mice. And IL-4, IL-13, phospho-Janus kinase 1, and P-STAT6 expressions presented a higher increase in the Tespa1-/-mouse model than in the WT mouse model. Further in vitro studies con rmed that IL-4 could more signi cantly promote tryptase and P-STAT6 activities in Tespa1-/-mast cells than their WT counterparts. Correlation analysis results showed a negative correlation between Tespa1 and P-STAT6. Immunoprecipitation results showed a direct link between Tespa1 and P-STAT6. Conclusions Altogether, our results indicate that Tespa1 can negatively regulate mast cell activity, and this event is related to the mast cell IL-4/STAT6 signaling pathway and could be therapeutically exploited to treat asthma attacks. Background Mast cells play an important role in the innate and adaptive immunities related to the pathophysiologic process of asthma. Mast cells not only act as effector cells during allergic reactions, but also perform a complex role in the induction and regulation of adaptive immune responses of asthma [1-3]. When an allergen enters the atopic patient, IgE is speci cally synthesized by B lymphocytes and bind to the higha nity IgE receptor (FcεRI) on the surface of mast cells and basophils [4, 5]. If the allergen re-enters the body, it can bind with IgE FcεRI on the mast cells, thus promoting cell activation, synthesizing and releasing various active mediators, such mediators as histamine, chemokine, neutrophil chemokine, prostaglandin [6, 7]. These mediators and cytokines play a pivotal role in the pathogenesis of asthma and in ammation. Interleu...

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“…Tespa1 regulates T cell receptor (TCR) signaling through direct binding to PLCγ1 and IP3R1, thereby facilitating TCR-induced calcium signals and thymocyte development. It also participates in mitochondrial Ca 2+ uptake via mitochondria-associated ER membranes in T cells ( 15 – 18 ). Furthermore, Tespa1 was also found to negatively regulate FcεRI-mediated signaling and mast cell-mediated allergic responses ( 18 ).…”

Section: Introductionmentioning

confidence: 99%

“…It also participates in mitochondrial Ca 2+ uptake via mitochondria-associated ER membranes in T cells ( 15 – 18 ). Furthermore, Tespa1 was also found to negatively regulate FcεRI-mediated signaling and mast cell-mediated allergic responses ( 18 ). Besides T cells and mast cells, Tespa1 is also highly expressed in most subsets of peripheral B cells, suggesting a potential role in B cell function ( 19 , 20 ).…”

Section: Introductionmentioning

confidence: 99%

Tespa1 Deficiency Dampens Thymus-Dependent B-Cell Activation and Attenuates Collagen-Induced Arthritis in Mice

Yao

Huang

et al. 2018

Front. Immunol.

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Thymocyte-expressed, positive selection-associated 1 (Tespa1) plays an important role in both T cell receptor (TCR)-driven thymocyte development and in the FcεRI-mediated activation of mast cells. Herein, we show that lack of Tespa1 does not impair B cell development but dampens the in vitro activation and proliferation of B cells induced by T cell-dependent (TD) antigens, significantly reduces serum antibody concentrations in vivo, and impairs germinal center formation in both aged and TD antigen-immunized mice. We also provide evidence that dysregulated signaling in Tespa1-deficient B cells may be linked to CD40-induced TRAF6 degradation, and subsequent effects on 1-phosphatidylinositol-4,5-bisphosphate phosphodiesterase gamma-2 (PLCγ2) phosphorylation, MAPK activation, and calcium influx. Furthermore, we demonstrate that Tespa1 plays a critical role in pathogenic B cells, since Tespa1-deficient chimeric mice showed a lower incidence and clinical disease severity of collagen-induced arthritis. Overall, our study demonstrates that Tespa1 is essential for TD B cell responses, and suggests an important role for Tespa1 during the development of autoimmune arthritis.

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Tespa1 regulates T cell receptor-induced calcium signals by recruiting inositol 1,4,5-trisphosphate receptors

Cited by 31 publications

References 26 publications

Tespa1 plays a role in the modulation of airway hyperreactivity through the IL-4/STAT6 pathway

Tespa1 plays a role in the modulation of airway hyperreactivity through the IL-4/STAT6 pathway

Tespa1 Negatively Modulates Asthmatic Attack Is Associated with IL-4/STAT-6 Pathway of Mast Cell

Tespa1 Deficiency Dampens Thymus-Dependent B-Cell Activation and Attenuates Collagen-Induced Arthritis in Mice

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