Networks involved in the calibration of T cell activation thresholds at University of Birmingham on FindAPhD.com

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Dr David Bending No more applications being accepted Competition Funded PhD Project (Students Worldwide)

About the Project

T cells are an essential population of lymphocytes that co-ordinate adaptive immune responses. T cell function is heavily dependent on their T cell receptors (TCRs) which respond to peptide fragments (called antigens) presented to them by antigen presenting cells (APCs). We have recently shown that in certain contexts, high amounts of antigen render T cells refractory to further restimulation. This is in part due to the upregulation of immune checkpoints, such as PD1, Lag3 and CTLA4 on the cell surface, that act to restrain TCR signalling, as reported using a novel TCR reporter system. Whilst immune checkpoint expression can account for some of this resistance to restimulation, we hypothesise that T cells also undergo rapid re-wiring of downstream intracellular signalling networks. In this project, we will employ state of the art in vivo research tools to investigate the intracellular signalosome in T cells that are rendered refractory to further stimulation. Proteomic analysis will be used to inform network approaches to make predictions about key pathways that may contribute to the raising of T cell activation thresholds. These can then be tested in a variety of in vitro and in vivo immunology models. This project will therefore gain insight into how T cells sense and adapt to antigen in their environment, providing fundamental insight into the workings of the immune system.

Techniques that will be undertaken during the project:

In vivo immunology models – immunisation, analysis of T cell responses, Flow cytometry, Proteomics, RNA sequencing, Bioinformatics (training provided, Network analysis, Systems biology modelling

Training for all techniques will be provided at a level suitable for the candidates. Specifically, candidates from the life sciences will be trained on computational/mathematical methods.

HOW TO APPLY:

About the MIBTP PhD Programme: https://warwick.ac.uk/mibtp/ https://www.birmingham.ac.uk/research/activity/mibtp/index.aspx

Details of project are listed: https://warwick.ac.uk/fac/cross_fac/mibtp/pgstudy/phd_opportunities/immunology2022/networks/

Informal enquiries to Dr David Bending [Email Address Removed]

Funding Notes

This is a 4 year BBSRC-fully funded doctoral fellowship. Call open to home, European and international students. For more details on the project, informal enquiries and/or advice on making your application, please contact Dr David Bending. More details of the PhD programme and eligibility see here:
https://warwick.ac.uk/fac/cross_fac/mibtp/pgstudy/phd_opportunities/application/

References

1. Elliot TAE, Jennings EK, Lecky DAJ, Thawait N, Flores-Langarica A, Copland A, Maslowski KM, Wraith DC, Bending D. Antigen and checkpoint receptor engagement recalibrates T cell receptor signal strength. IMMUNITY. 2021. DOI: https://doi.org/10.1016/j.immuni.2021.08.020
2. Jennings EK, Lecky DAJ, Ono M, Bending D. Application of dual Nr4a1-GFP and Nr4a3-Tocly reporter mice to study T cell receptor signaling by flow cytometry. STAR PROTOCOLS. 2021;2(1):100284
3. Jennings EK, Elliot TAE, Thawait N, Yam-Puc JC, Kanabar S, Ono M, Toellner KM, Wraith DC, Anderson G, Bending D. Nr4a1 and Nr4a3 reporter mice are differentially sensitive to T cell receptor signal strength and duration. CELL REPORTS. 2020;33:108328

Where will I study?

University of Birmingham

We work to provide the best possible teaching, research facilities and support services to ensure our postgraduates reach the peak of their potential.

Networks involved in the calibration of T cell activation thresholds

University of Birmingham College of Medical and Dental Sciences