Completed Cancer Cells, Biochemistry & Physiology

Serine kinase pathways that determine T lymphocyte activation and cell fate choices.

Funder Wellcome Charity-funded
Recipient organisation University of Dundee
Funding £5.6M
Period Oct 2012 — Sept 2022

In plain English

AI plain-English summary

A single protein, mTOR, acts as a master switch inside immune cells, deciding whether a T cell should attack an infection, remember a past pathogen, or quiet down. The problem is that this decision-making process often goes wrong. When T cells misread signals from nutrients, cytokines, or antigens, they can launch autoimmune attacks, fail to clear infections, or become exhausted in tumours. Researchers know mTOR is central, but they do not fully understand how it, along with kinases like PKB and AMPK, coordinates the thousands of other proteins inside a T cell. This project will map the entire set of phosphorylated proteins—the phosphoproteome—in different T cell subtypes, using high-resolution mass spectrometry. It will also test how these signals control two key transcription factors, Foxo1 and KLF2, which govern T cell fate. This is fundamental science. There is no immediate clinical application. But a comprehensive map of T cell signalling pathways would be a public resource for the immunology community. Similar foundational work on kinase pathways has previously led directly to targeted cancer therapies. A deeper understanding of how T cells balance activation and quiescence could eventually inform new strategies for vaccine design, autoimmune disease treatment, and cancer immunotherapy.

View original technical description
The laboratory will explore how mTOR (mammalian target of rapamycin), Protein Kinase B (PKB), Protein Kinase D2 (PKD2) and the AMP-activated Protein Kinase alpha1 (AMPKalpha1) integrate antigen receptor, cytokine and nutrient signalling to control T cell metabolism, cytokine production and T cell migration/trafficking. One focus will be the transcription factors Foxo1 and KLF2 because these molecules integrate signalling by mTOR, PKB and AMPK to control T cell fate. One core technology will be high resolution mass spectrometry to map the proteome and phosphoproteome of T lymphocyte subpopulations and to define Foxo1 and KLF2 protein complexes. Phosphoproteomic analysis of CD8 cytotoxic T cells has revealed links between serine/threonine kinases and chromatin regulators. The future program will test the concepts generated by this work but additionally define the phosphoproteome of na ve T cells and CD4 T cell subpopulations. The functional relevance of the biochemical data will be inte rrogated rigorously using bioinformatics, mouse molecular genetics and analysis of T cell function in vivo. The experiments to comprehensively map T cell phosphoproteomes will be a valuable community resource and reveal the signalling pathways that maintain the essential epigenetic and transcriptional programs that define how peripheral T cells control metabolism and function.

View the original record at the funder ↗

Researchers

Doreen Cantrell (EPMC Awardee)

Related Research

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Original classification

Principal Research Fellowship Renewal

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