Integrative Proteomics and Phosphoproteomics Profiling Reveals Dynamic Signaling Networks and Bioenergetics Pathways Underlying T Cell Activation
Open accessAbstract
The molecular circuits by which antigens activate quiescent T cells remain poorly understood. We combined temporal profiling of the whole proteome and phosphoproteome via multiplexed isobaric labeling proteomics technology, computational pipelines for integrating multi-omics datasets, and functional perturbation to systemically reconstruct regulatory networks underlying T cell activation. T cell receptors activated the T cell proteome and phosphoproteome with discrete kinetics, marked by early dynamics of phosphorylation and delayed ribosome biogenesis and mitochondrial activation. Systems biology analyses identified multiple functional modules, active kinases, transcription factors and connectivity between them, and mitochondrial pathways including mitoribosomes and complex IV. Genetic perturbation revealed physiological roles for mitochondrial enzyme COX10-mediated oxidative phosphorylation in T cell quiescence exit. Our multi-layer proteomics profiling, integrative network analysis, and functional studies define landscapes of the T cell proteome and phosphoproteome and reveal signaling and bioenergetics pathways that mediate lymphocyte exit from quiescence.
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FOXK2 and NR4A1 are activated at 8 h based on regulon activity, consistent with whole proteomics and phosphoproteomics data.
“FOXK2 and NR4A1 are activated at 8 h based on regulon activity (Fig. 6d), which is consistent with the whole proteomics and phosphoproteomics data (Fig. 6e)76.”
From Inferring gene regulatory networks from single-cell multiome data using atlas-scale external data (2025) · cites this paper as [76]
The Results section on TCR-stimulated proteome changes places NR4A1 in a whole-proteome cluster that rises at 2 h and then gradually declines. The cited paper does not establish FOXK2 or NR4A1 activation at 8 h based on regulon activity, nor does the retrieved phosphoproteomics discussion show matching changes for those factors. Its NR4A1 finding therefore supports only part of the claimed consistency. (LLM, conf=0.84)
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Metabolic waypoints during T cell differentiation
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Novel specialized cell state and spatial compartments within the germinal center
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Nutrients: Signal 4 in T cell immunity
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DEPTOR at the Nexus of Cancer, Metabolism, and Immunity
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Self-citationThe metabolic spectrum of memory T cells
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Self-citationDynamic Post-Transcriptional Events Governing CD8+ T Cell Homeostasis and Effector Function
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Self-citationFever supports CD8 + effector T cell responses by promoting mitochondrial translation
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Self-citationThe Importance of Metabolism for Immune Homeostasis in Allergic Diseases
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Mitochondria during T cell aging
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Self-citationACLY and ACSS2 link nutrient-dependent chromatin accessibility to CD8 T cell effector responses
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Mitochondrial respiration is necessary for CD8+ T cell proliferation and cell fate
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- Authors
- Tan, H., Yang, K., Li, Y., Shaw, T. I., Wang, Y., Blanco, D. B., Wang, X., Cho, J.-H., Wang, H., Rankin, S., Guy, C., Peng, J., & Chi, H.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Corresponding author
- Peng, Junmin
- Chi, Hongbo
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2017-03
- Volume
- 46
- Issue
- 3
- Pages
- 488-503
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC5466820
- OpenAlex
- W2593643932
- Cited by
- 372
- References
- 39
- Citations by year
- 2026: 23 · 2025: 50 · 2024: 59 · 2023: 37 · 2022: 43 · 2021: 49 · 2020: 48 · 2019: 32 · 2018: 19 · 2017: 12
- FWCI
- 14.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (AG047928, GM114260, AI101407, CA176624, AI105887, NS064599, P30CA021765)
- American Asthma Foundation
- ALSAC
- Topics
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Keywords
- T cell activation, T cell receptor signaling, T cell proteome, phosphorylation dynamics, ribosome biogenesis, mitochondrial activation, mitochondrial ribosome, mitochondrial complex IV, oxidative phosphorylation, COX10, T cell quiescence, bioenergetics, signaling networks, transcription factors, kinases
- MeSH terms
- Animals, Energy Metabolism, Lymphocyte Activation, Membrane Proteins, Mice, Inbred C57BL, Phosphorylation, Receptors, Antigen, T-Cell, Mass Spectrometry, T-Lymphocytes, Signal Transduction, Alkyl and Aryl Transferases, Proteomics, Mice
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