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Understanding the role of immune checkpoints in the regulation of T-cell migration

Primary Supervisor: Dr Alex Wadley, School of Sport, Exercise and Rehabilitation Sciences

Secondary supervisor: Dr Sarah Aldred & Dr Parth Narendran

PhD project title: Understanding the role of immune checkpoints in the regulation of T-cell migration

University of Registration: University of Birmingham

Project outline:

Background
A healthy immune system can recognise and respond to foreign bodies such as bacteria/ viruses and damaged cells/ tissues, through a complex network of mechanisms that allow the migration of immune cells, such as T-cell lymphocytes between blood and tissues. In auto-immunity, immune cell function is disrupted and T-cells begin to migrate uncontrollably, subsequently damaging certain tissues and compromising health.

Immune checkpoint receptors, such as Programmed-Death Receptor-1 (PD-1) and Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) are critical negative regulators of T-cell activity. Recent evidence also suggests that these receptors play a crucial role in modulating T-cell migration into tissues, by regulating the dwell time of antigenic peptide presentation to the T-cell receptor, and upregulating the expression of chemokine receptors that promote T-cell migration. Despite this, low expression of these receptors initiates a heightened state of T-cell activation that drives aberrant migration of T-cells into tissues. Mechanistic studies in humans are sparse in this area, as well as an understanding of the lifestyle factors that drive these immune responses, which are crucial for maintaining long-term health.

Preliminary data from our laboratory suggests that exercise can increase the circulating concentration of T-cells expressing PD-1 (PD-1+), as well as increasing the expression of PD-1 within each T-cell. We suggest that being more physically active throughout the lifespan may be an effective strategy to boost immune checkpoint receptor expression on immune cells, thus controlling the activation and migration of immune cells into tissues and maintaining immune system health.

Aims & Objectives
This project will use acute and chronic exercise models in humans to assess the effect of exercise on T-cell phenotype and antigen-specific migration. The project will explore the role of immune checkpoint receptors in governing these functional responses, to better understand the role of exercise in maintaining immune system health.
In this project:

  1. You will characterise immune checkpoint receptor expression in human T-cells.
  2. You will investigate the role of PD-1 and CTLA-4 receptors in T-cell migration by undertaking functional T-cell migration assays that manipulate PD-1 and CTLA-4.
  3. You will investigate the mechanisms by which acute and regular exercise regulate immune cell phenotype and migration.

BBSRC Strategic Research Priority: Understanding the Rules of Life: Immunology

    Techniques that will be undertaken during the project:

    • Cell culture
    • Magnetic cell separation of immune cell populations
    • Multi-parameter flow cytometry
    • Tetramer assays to identify antigen specific immunity
    • Functional ex vivo T-cell assays (e.g. chemotaxis and cell proliferation)
    • ELISA

    Contact: Dr Alex Wadley, University of Birmingham