Kinome Profiling of Regulatory T Cells: A Closer Look into a Complex Intracellular Network

Tuettenberg, Andrea; Hahn, Susanne A.; Mazur, Johanna; Gerhold‐Ay, Aslihan; Scholma, Jetse; Marg, Iris; Ulges, Alexander; Satoh, Kaneo; Bopp, Tobias; Joore, Jos; Jonuleit, Helmut

doi:10.1371/journal.pone.0149193

Cited by 7 publications

(6 citation statements)

References 38 publications

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“…The WFA-specific phosphopeptidome analyses performed here revealed specific repression of various phospho-Tyr and phospho-Ser/Thr peptides, which is consistent with previous whole cell phosphoproteomics performed in activated T-cells (17). Previously, we and others have demonstrated the importance of ZAP70, PKC isoforms, AKT, TALIN1, and MAPK signalling pathways in LFA-1induced T-cell migration (18,19).…”

Section: Discussionsupporting

confidence: 91%

Withaferin A inhibits LFA-1-stimulated ZAP70 activity and T-cell motility

Turabe

Chirumamilla

Perez-Novo

et al. 2021

Preprint

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Here we report that a steroidal lactone withaferin A (WFA) can inhibit T-cell motility, which is crucial for adaptive immune responses as well as autoimmune reactions. Tandem mass spectrometry identified WFA-interactome in human T-cells that were stimulated to migrate via cross-linking of the lymphocyte function-associated antigen-1 (LFA-1) integrin with the ligand intercellular adhesion receptor 1 (ICAM-1). Data revealed significant enrichment of the zeta-chain-associated protein kinase 70 (ZAP70) and cytoskeletal actin protein interaction networks. Phospho-peptide mapping and kinome analysis substantiated kinase signaling downstream of ZAP70 and cytoskeletal kinase pathways as key WFA targets, which was further confirmed by in silico analysis and molecular assays. The WFA-ZAP70 complex was disrupted by a redox agent dithiothreitol, suggesting a covalent binding interface. Moreover, WFA ablated the phosphorylation of the myosin light chain, further constraining T-cell motility. These studies identify a mechanism whereby WFA can impact T-cell motility. WFA can therefore be exploited to pharmacologically controlling host immune responses and preventing autoimmune-mediated pathologies.

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Section: Discussionsupporting

confidence: 91%

Withaferin A inhibits LFA-1-stimulated ZAP70 activity and T-cell motility

Turabe

Chirumamilla

Perez-Novo

et al. 2021

Preprint

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“…We showed that both in Th2 cells as well as in T regs the EGFR is strongly upregulated upon activation . Also, kinome profiling in human T regs revealed that the EGFR is one of the strongest upregulated kinases upon T reg activation . In line with these findings, the group of Rosenblum found induced EGFR expression in T regs in a model of skin wounding in mice, and lineage‐specific deletion of EGFR in T regs resulted in reduced T reg accumulation within the inflamed skin .…”

Section: The Function Of Regulatory T‐cell‐derived Amphiregulinsupporting

confidence: 62%

“…32,43 Also, kinome profiling in human T regs revealed that the EGFR is one of the strongest upregulated kinases upon T reg activation. 55 In line with these findings, the group of Rosenblum found induced EGFR expression in T regs in a model of skin wounding in mice, 12 and lineagespecific deletion of EGFR in T regs resulted in reduced T reg accumulation within the inflamed skin. 12 Thus, in this respect the phenotype of EGFR-and T1/ST2-deficient T regs resembles each other, with both depicting a deficiency to expand at the site of inflammation.…”

Section: The Function Of Regulatory T-cell-derived Amphiregulinmentioning

confidence: 73%

Immune‐ and non‐immune‐mediated roles of regulatory T‐cells during wound healing

2019

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Summary The immune system has a well‐established contribution to tissue homeostasis and wound healing. However, in many cases immune responses themselves can cause severe tissue damage. Thus, the question arose to which extent cells of the immune system directly contribute to the process of wound healing and to which extent the resolution of excessive immune responses may indirectly contribute to wound healing. FoxP3‐expressing CD4 T‐cells, so‐called regulatory T‐cells (Tregs), have an important contribution in the regulation of immune responses; and, in recent years, it has been suggested that Tregs next to an immune‐regulatory, ‘damage‐limiting’ function may also have an immune‐independent ‘damage‐resolving’ direct role in wound healing. In particular, the release of the epidermal growth factor‐like growth factor Amphiregulin by tissue‐resident Tregs during wound repair suggested such a function. Our recent findings have now revealed that Amphiregulin induces the local release of bio‐active transforming growth factor (TGF)β, a cytokine involved both in immune regulation as well as in the process of wound repair. In light of these findings, we discuss whether, by locally activating TGFβ, Treg‐derived Amphiregulin may contribute to both wound repair and immune suppression. Furthermore, we propose that Treg‐derived Amphiregulin in an autocrine way may enable an IL‐33‐mediated survival and expansion of tissue‐resident Tregs upon injury. Furthermore, Treg‐derived Amphiregulin may contribute to a constitutive, low‐level release of bio‐active TGFβ within tissues, leading to continuous tissue regeneration and to an immune‐suppressive environment, which may keep inflammation‐prone tissues in an homeostatic state.

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“…The populations of regulatory T-cells (Treg) [19] are the leading factor of immunological homeostasis. Treg cells interfere with the activation of effector T lymphocytes involved in autoimmune and allergic processes, and, at the same time, reduce antitumor immunity.…”

Section: Expression Of Genes Nk-lysin Blvr Ifn- In Peripheral Bloomentioning

confidence: 99%

EXPRESSION of NK-lysin, blvr, ifn-a AND BLOOD CELL POPULATIONS IN COWS INFECTED BY BOVINE LEUKEMIA VIRUS

Kosovskii¹,

Glazko²,

Kovalchuk³

et al. 2017

S-h. biol.

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At now, it is impossible to prevent or control the spread of retroviral infections, in particular, bovine leukemia virus (BLV). The existing methods of vaccination and detection of infected animals remain insufficient (G. Gutiérrez et al., 2014; M. Nishiike et al., 2016) which necessitates further investigations of the interactions between pathogen and host organism. Previously, we obtained evidence that a common characteristic for BLV infected animals with moderate and high leukocytosis was the increase in platelets, and in cows with a pronounced leukocytosis the decrease in the number of neutrophils (G.Yu. Kosovovskii et al. 2017). In order to assess the relationship between BLV infection in animals, the ratio of cell populations in the peripheral blood and the expression of the genes, encoding the BLV receptor (blvr gene), a comparative analysis of antivirus protection protein, interferon alpha (INFΑ), and effector protein of innate immunity, NK-lysine, was carried out in two groups of cows that differed in origin and farm conditions. In result, the evidences were obtained that cows from two farms differed mainly in the amount of peripheral blood neutrophils and platelets. However, in both farms the BLV infected animals had the reduced gene expression of NK-lysine and an increased number of platelets compared to cows free from infection. Relatively increased expression of blvr was observed in BLV infected cows, reflecting, apparently, the increase in the proportion of the young forms of B-lymphocytes (M. Lavanya et al., 2008). On the basis of the own obtained findings and literature data the scheme is proposed of the influence of BLV on the expression of NK-lysine and the suppression of apoptosis. As per the scheme, viral protein TAX (a transcription activator) induces the expression of host tnf- gene (M. Arainga et al., 2012) which, in turn, activates the Treg regulators of immune homeostasis (L.Y. Chang et al., 2015); Treg produces TGF-β (transforming growth factor beta), TGF-β inhibits the proliferation and activity of T-killers and NK-cells, the producers of NK-lysine, and increases the number and activity of platelets which inhibits the apoptosis (K. Ohira et al., 2016; S.C. Tao et al., 2016). The proposed scheme suggested that the key event in pathogenesis, induced by BLV, is the effect on the innate immune system.

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Kinome Profiling of Regulatory T Cells: A Closer Look into a Complex Intracellular Network

Cited by 7 publications

References 38 publications

Withaferin A inhibits LFA-1-stimulated ZAP70 activity and T-cell motility

Withaferin A inhibits LFA-1-stimulated ZAP70 activity and T-cell motility

Immune‐ and non‐immune‐mediated roles of regulatory T‐cells during wound healing

EXPRESSION of NK-lysin, blvr, ifn-a AND BLOOD CELL POPULATIONS IN COWS INFECTED BY BOVINE LEUKEMIA VIRUS

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