ArticleThe Journal of biological chemistry2019
T cells transduce T-cell receptor signal strength by generating different phosphatidylinositols.
Article in The Journal of biological chemistry, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 30 citations in OpenAlex.
- CD8Cell reports. Medicine · 2026Review
- Basal phosphorylation of SHIP1 by Lyn suppresses proinflammatory signaling in the absence of a phagocytic synapse.Journal of immunology (Baltimore, Md. : 1950) · 2026Article
- Regulation of TCR-induced Transcriptional Kinetics by Interleukin 2-inducible T Cell Kinase (ITK) in CD8bioRxiv : the preprint server for biology · 2025Article
- Ndrg3 is a critical regulator of peripheral T cell maturation and homeostasis.Science advances · 2025Article
- The phospholipid kinase PIKFYVE is essential for Th17 differentiation.The Journal of experimental medicine · 2025Article
- The mTORC2 signaling network: targets and cross-talks.The Biochemical journal · 2024Review
- Phosphoinositide acyl chain saturation drives CD8Nature immunology · 2023Article
- Recent insights into the role of Akt in CD4 T-cell activation and differentiation: alternative splicing and beyond.Immunometabolism (Cobham, Surrey) · 2023Review
- The role of metabolism on regulatory T cell development and its impact in tumor and transplantation immunity.Frontiers in immunology · 2022Review
- Signal strength controls the rate of polarization within CTLs during killing.The Journal of cell biology · 2021Article
- Strength and Numbers: The Role of Affinity and Avidity in the 'Quality' of T Cell Tolerance.Cells · 2021Review
- Regulatory T Cells Fail to Suppress Fast Homeostatic Proliferation In Vitro.Life (Basel, Switzerland) · 2021Article
- Modeling the Th17 and Tregs Paradigm: Implications for Cancer Immunotherapy.Frontiers in cell and developmental biology · 2021Review
- The phosphoinositide regulatory network in Trypanosoma brucei: Implications for cell-wide regulation in eukaryotes.PLoS neglected tropical diseases · 2020Review
- Transforming growth factor β (TGF-β) receptor signaling regulates kinase networks and phosphatidylinositol metabolism during T-cell activation.The Journal of biological chemistry · 2020Article
- Age-related transcriptional modules and TF-miRNA-mRNA interactions in neonatal and infant human thymus.PloS one · 2020Article
- Interleukin-27 Enforces Regulatory T Cell Functions to Prevent Graft-versus-Host Disease.Frontiers in immunology · 2020Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
T-cell receptor (TCR) signaling strength is a dominant factor regulating T-cell differentiation, thymic development, and cytokine signaling. The molecular mechanisms by which TCR signal strength is transduced to downstream signaling networks remains ill-defined. Using computational modeling, biochemical assays, and imaging flow cytometry, we found here that TCR signal strength differentially generates phosphatidylinositol species. Weak TCR signals generated elevated phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and reduced phosphatidylinositol (3,4,5)-trisphosphate (PIP3) levels, whereas strong TCR signals reduced PI(4,5)P2 and elevated PIP3 levels. A proteomics screen revealed that focal adhesion kinase bound PI(4,5)P2, biochemical assays disclosed that focal adhesion kinase is preferentially activated by weak TCR signals and is required for optimal Treg induction, and further biochemical experiments revealed how TCR signaling strength regulates AKT activation. Low PIP3 levels generated by weak TCR signals were sufficient to activate phosphoinositide-dependent kinase-1 to phosphorylate AKT on Thr-308 but insufficient to activate mTOR complex 2 (mTORC2), whereas elevated PIP3 levels generated by a strong TCR signal were required to activate mTORC2 to phosphorylate Ser-473 on AKT. Our results provide support for a model that links TCR signaling to mTORC2 activation via phosphoinositide 3-kinase signaling. Together, the findings in this work establish that T cells measure TCR signal strength by generating different levels of phosphatidylinositol species that engage alternate signaling networks to control cell fate decisions.
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