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Investigating 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, UoB & Dr Parth Narendran, UoB

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

University of Registration: University of Birmingham

Project outline:

A healthy immune system can recognise and respond to foreign bodies such as bacteria and viruses or damaged cells and tissues through a complex network of mechanisms. This response is facilitated by the migration of immune cells, such as T-cell lymphocytes between blood and tissues. T cells orchestrate a diverse range of immune functions, such as controlling infection, eradicating cancer, mediating allergic reactions, and promoting successful vaccinations. These functions are exquisitely specific and tightly regulated; however, when dysregulated, T cells can act indiscriminately. This drives autoimmune reactions, whereby T cells aberrantly migrate towards the body’s own tissues, causing damage 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 indicates that these receptors play a role in modulating T-cell migration into tissues. Despite this, low expression of these receptors initiates a heightened state of T-cell activation that drives aberrant migration of T-cells into tissues. Understanding the precise roles of PD-1 and CTLA-4 in mediating T cell migration in humans are therefore critical for understanding their role in autoimmunity and wider immune system health. Furthermore, the factors that modulate immune checkpoint expression and function are important for developing therapeutic approaches for maintaining long-term health and offsetting the development of autoimmunity.

The incidence of autoimmune illness is rising in the UK between 3-9% annually. The factors underpinning this current trajectory are unclear, but are believed to relate to changes in our environment and also lifestyle choices, such as levels of physical activity. Regular bouts of moderate-intensity physical activity confer protection against many immune and inflammatory disorders, as well as against multi-morbidity and mortality. Published data from this research team indicate that single bouts of exercise can increase the circulating concentration of T-cells expressing PD-1 in blood, as well as increasing the expression of PD-1 on the surface of each T-cell. Furthermore, the concentration of soluble immune checkpoints increase in blood plasma after exercise. This data indicates that exercise may modulate the activation state of T cells in blood, thus providing a rationale to further explore its role in modulating T cell migration.

This PhD programme will investigate the role of immune checkpoint receptors in governing T cell migration in healthy individuals and those with autoimmune disease. Furthermore, projects will interrogate how physical activity modulates immune checkpoint expression and function, thus providing insight into the role of physical activity to maintain immune system health and offset autoimmunity.

In this project:

  1. You will investigate the role of PD-1 and CTLA-4 in governing T-cell migration by employing functional T-cell migration assays that manipulate PD-1 and CTLA-4 activity.
  2. You will undertake cross-sectional and longitudinal studies in humans, to investigate the role of physical activity in regulating immune checkpoints, and subsequent impact on T cell migration.

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

        Techniques that will be undertaken during the project:

        • Cell sorting and multi-parameter flow cytometry
        • Functional immune assays (e.g. migration, cytotoxicity and metabolic flux)
        • Peptide-human leukocyte antigen (pHLA) class I tetramers assays
        • ELISA
        • Human intervention studies

        Contact: Dr Alex Wadley, University of Birmingham