Induction of CD4+ regulatory T cells by stimulation with Staphylococcal Enterotoxin C2 through different signaling pathways

Li, Yongqiang; Xu, Mingkai; Li, Yansheng; Zhang, Zhichun; Gu, Weizhong; Halimu, Gulinare; Li, Yuqi; Zhang, Huiwen; Zhang, Chenggang

doi:10.1016/j.biopha.2021.112204

Cited by 2 publications

(3 citation statements)

References 51 publications

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“…Selective inhibition of PI3K and PLCγ signaling pathways, which has been shown to play an important role in Tregs induction, significantly reduced the levels of SEC2-induced Tregs. IL-2 along with STAT5 phosphorylation proved to be important in the induction of Tregs by SEC2 [110]. The same effect was observed in IL-2/STAT5 signaling, which is needed for FoxP3 expression and the ultimate induction of Tregs [114].…”

Section: Regulatory T Cellsmentioning

confidence: 66%

“…On the other hand, the efficacy of Staphylococcal Enterotoxin C2 (SEC2) as cancer immunotherapy by its ability to induce Tregs immunosuppressive function is questionable [110]. The SEC2 is a superantigen that connects MHC class II to TCR, resulting in hyperactivation of resting T cells [111].…”

Section: Regulatory T Cellsmentioning

confidence: 99%

“…The stimulation of TGF-β needed for the expression of Tregs and their regulatory roles in the immune system is well studied [123]. Hence blocking the TGF-β/SMAD signaling pathway downregulates the SEC2-induced Tregs differentiation [110].…”

Section: Regulatory T Cellsmentioning

confidence: 99%

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Immunosuppressive Signaling Pathways as Targeted Cancer Therapies

et al. 2022

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Immune response has been shown to play an important role in defining patient prognosis and response to cancer treatment. Tumor-induced immunosuppression encouraged the recent development of new chemotherapeutic agents that assists in the augmentation of immune responses. Molecular mechanisms that tumors use to evade immunosurveillance are attributed to their ability to alter antigen processing/presentation pathways and the tumor microenvironment. Cancer cells take advantage of normal molecular and immunoregulatory machinery to survive and thrive. Cancer cells constantly adjust their genetic makeup using several mechanisms such as nucleotide excision repair as well as microsatellite and chromosomal instability, thus giving rise to new variants with reduced immunogenicity and the ability to continue to grow without restrictions. This review will focus on the central molecular signaling pathways involved in immunosuppressive cells and briefly discuss how cancer cells evade immunosurveillance by manipulating antigen processing cells and related proteins. Secondly, the review will discuss how these pathways can be utilized for the implementation of precision medicine and deciphering drug resistance.

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Section: Regulatory T Cellsmentioning

confidence: 66%

Section: Regulatory T Cellsmentioning

confidence: 99%

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Immunosuppressive Signaling Pathways as Targeted Cancer Therapies

et al. 2022

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Stimulation Strength Determined by Superantigen Dose Controls Subcellular Localization of FOXP3 Isoforms and Suppressive Function of CD4+CD25+FOXP3+ T Cells

Lee,

Park,

Nicosia

et al. 2023

The Journal of Immunology

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Staphylococcal superantigens induce massive activation of T cells and inflammation, leading to toxic shock syndrome. Paradoxically, increasing evidence indicates that superantigens can also induce immunosuppression by promoting regulatory T cell (Treg) development. In this study, we demonstrate that stimulation strength plays a critical role in superantigen-mediated induction of immunosuppressive human CD4+CD25+FOXP3+ T cells. Suboptimal stimulation by a low dose (1 ng/ml) of staphylococcal enterotoxin C1 (SEC1) led to de novo generation of Treg-like CD4+CD25+FOXP3+ T cells with strong suppressive activity. In contrast, CD4+CD25+ T cells induced by optimal stimulation with high-dose SEC1 (1 µg/ml) were not immunosuppressive, despite high FOXP3 expression. Signal transduction pathway analysis revealed differential activation of the PI3K signaling pathway and expression of PTEN in optimal and suboptimal stimulation with SEC1. Additionally, we identified that FOXP3 isoforms in Treg-like cells from the suboptimal condition were located in the nucleus, whereas FOXP3 in nonsuppressive cells from the optimal condition localized in cytoplasm. Sequencing analysis of FOXP3 isoform transcripts identified five isoforms, including a FOXP3 isoform lacking partial exon 3. Overexpression of FOXP3 isoforms confirmed that both an exon 2–lacking isoform and a partial exon 3–lacking isoform confer suppressive activity. Furthermore, blockade of PI3K in optimal stimulation conditions led to induction of suppressive Treg-like cells with nuclear translocation of FOXP3, suggesting that PI3K signaling impairs induction of Tregs in a SEC1 dose-dependent manner. Taken together, these data demonstrate that the strength of activation signals determined by superantigen dose regulates subcellular localization of FOXP3 isoforms, which confers suppressive functionality.

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Induction of CD4+ regulatory T cells by stimulation with Staphylococcal Enterotoxin C2 through different signaling pathways

Cited by 2 publications

References 51 publications

Immunosuppressive Signaling Pathways as Targeted Cancer Therapies

Immunosuppressive Signaling Pathways as Targeted Cancer Therapies

Stimulation Strength Determined by Superantigen Dose Controls Subcellular Localization of FOXP3 Isoforms and Suppressive Function of CD4+CD25+FOXP3+ T Cells

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