The kinase ITK controls a Ca2+-mediated switch that balances TH17 and Treg cell differentiation

IF 6.7 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Science Signaling Pub Date : 2024-07-23 DOI:10.1126/scisignal.adh2381
Orchi Anannya, Weishan Huang, Avery August
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Abstract

The balance of proinflammatory T helper type 17 (TH17) and anti-inflammatory T regulatory (Treg) cells is crucial for immune homeostasis in health and disease. The differentiation of naïve CD4+ T cells into TH17 and Treg cells depends on T cell receptor (TCR) signaling mediated, in part, by interleukin-2–inducible T cell kinase (ITK), which stimulates mitogen-activated protein kinases (MAPKs) and Ca2+ signaling. Here, we report that, in the absence of ITK activity, naïve murine CD4+ T cells cultured under TH17-inducing conditions expressed the Treg transcription factor Foxp3 and did not develop into TH17 cells. Furthermore, ITK inhibition in vivo during allergic inflammation increased the Treg:TH17 ratio in the lung. These switched Foxp3+ Treg-like cells had suppressive function, and their transcriptomic profile resembled that of differentiated, induced Treg (iTreg) cells, but their chromatin accessibility profiles were intermediate between TH17 and iTreg cells. Like iTreg cells, switched Foxp3+ Treg-like cells had reductions in the expression of genes involved in mitochondrial oxidative phosphorylation and glycolysis, in the activation of the mechanistic target of rapamycin (mTOR) signaling pathway, and in the abundance of the TH17 pioneer transcription factor BATF. This ITK-dependent switch between TH17 and Treg cells depended on Ca2+ signaling but not on MAPKs. These findings suggest potential strategies for fine-tuning TCR signal strength through ITK to control the balance of TH17 and Treg cells.
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激酶 ITK 可控制 Ca2+ 介导的开关,从而平衡 TH17 和 Treg 细胞的分化。
促炎 T 辅助细胞 17 型(TH17)和抗炎 T 调节细胞(Treg)的平衡对健康和疾病中的免疫平衡至关重要。幼稚 CD4+ T 细胞向 TH17 和 Treg 细胞的分化依赖于 T 细胞受体(TCR)信号传导,部分由白细胞介素-2 诱导的 T 细胞激酶(ITK)介导,ITK 刺激丝裂原活化蛋白激酶(MAPKs)和 Ca2+ 信号传导。在这里,我们报告了在 ITK 活性缺失的情况下,在 TH17 诱导条件下培养的小鼠幼稚 CD4+ T 细胞会表达 Treg 转录因子 Foxp3,并且不会发育成 TH17 细胞。此外,在体内过敏性炎症期间抑制 ITK 会增加肺中 Treg 与 TH17 的比例。这些切换的Foxp3+ Treg样细胞具有抑制功能,它们的转录组特征与分化的诱导Treg(iTreg)细胞相似,但它们的染色质可及性特征介于TH17和iTreg细胞之间。与 iTreg 细胞一样,切换后的 Foxp3+ Treg 样细胞也减少了参与线粒体氧化磷酸化和糖酵解的基因的表达、雷帕霉素机械靶标(mTOR)信号通路的激活以及 TH17 先驱转录因子 BATF 的丰度。这种 ITK 依赖性的 TH17 和 Treg 细胞之间的切换取决于 Ca2+ 信号,而不是 MAPK。这些发现提示了通过 ITK 微调 TCR 信号强度以控制 TH17 和 Treg 细胞平衡的潜在策略。
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来源期刊
Science Signaling
Science Signaling BIOCHEMISTRY & MOLECULAR BIOLOGY-CELL BIOLOGY
CiteScore
9.50
自引率
0.00%
发文量
148
审稿时长
3-8 weeks
期刊介绍: "Science Signaling" is a reputable, peer-reviewed journal dedicated to the exploration of cell communication mechanisms, offering a comprehensive view of the intricate processes that govern cellular regulation. This journal, published weekly online by the American Association for the Advancement of Science (AAAS), is a go-to resource for the latest research in cell signaling and its various facets. The journal's scope encompasses a broad range of topics, including the study of signaling networks, synthetic biology, systems biology, and the application of these findings in drug discovery. It also delves into the computational and modeling aspects of regulatory pathways, providing insights into how cells communicate and respond to their environment. In addition to publishing full-length articles that report on groundbreaking research, "Science Signaling" also features reviews that synthesize current knowledge in the field, focus articles that highlight specific areas of interest, and editor-written highlights that draw attention to particularly significant studies. This mix of content ensures that the journal serves as a valuable resource for both researchers and professionals looking to stay abreast of the latest advancements in cell communication science.
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