T and B Cell Development and Function

Tumour necrosis factor (TNF) is a ubiquitous inflammatory mediator, critical for immunity to pathogens and also a key driver of pathology in autoimmune and inflammatory diseases. We have identified unexpected roles for TNF signalling in development and maintenance of naïve T cells, and a novel TNF signalling mechanism that controls T cell survival. This programme investigates how inflammatory TNF signalling controls T cell function in immune responses and may lead to novel therapeutic approaches in autoimmune / autoinflammatory diseases.

Lead Investigators

• Professor Benedict Seddon (Institute of Immunity & Transplantation, UCL)

Collaborators

• Professor Pascal Meier (The Institute of Cancer Research, London)
• Professor Joyti Choudhary (The Institute of Cancer Research, London)

Funding

• Medical Research Council

The tumour microenvironment (TME) contains infiltrating T lymphocytes that mediate anti-tumour immunity, but also include regulatory T cells (Treg), a subset of Foxp3 expressing CD4+ T cells that are vital in preventing autoimmunity and immunopathology. Tregs in tumours suppresses host anti-tumour immunity and is associated with poor prognosis. In this project, we are investigating the mechanisms controlling the generation and maintenance of intratumoural Treg and may lead to novel therapies to block their undesirable activities.

Lead Investigators

• Professor Benedict Seddon (Institute of Immunity & Transplantation, UCL)

Collaborators

• Dr Simon Barry (Astrazeneca)

Funding

• Astrazeneca

Regulatory T cell (Treg) function is tightly controlled to maintain immune tolerance. Insufficient Treg function can lead to autoimmunity (eg. childhood arthritis, type-1 diabetes), while excess Treg function can promote cancer progression. We have defined specific Treg fitness gene and protein signatures that could be used as biomarkers for childhood arthritis to monitor disease activity (flare) and treatment response. We are now validating these signatures using nanoString, mathematical modelling and flow cytometry prior with the aim of translating our work into the clinic.

Lead Investigator

• Dr Anne Pesenacker (Institute of Immunity & Transplantation, UCL)

Collaborators

• Professor Lucy Wedderburn (Institute of Child Health, Centre for Adolescent Rheumatology, UCL-GOS)
• Dr Andreas Tiffeau-Mayer (Institute of Immunity & Transplantation, UCL)
• Professor Coziana Ciurtin (Centre for Adolescent Rheumatology, UCL)
• Dr Chris Wallace (MRC Biostatistics Unit, University of Cambridge)
• Professor Adam Croft (Institute of Inflammation and Ageing, University of Birmingham)

Funding

• NIHR BRC UCLH (closed)
• Versus Arthritis (VA Priorities Research Grant)

Signalling via co-stimulatory and co-inhibitory receptors control function of Tregs. Co-receptors, therefore, are good therapeutic targets for cancer and autoimmunity. The co-inhibitory and co-stimulatory receptors TIGIT and CD226 share ligands (CD155(PVR), CD112) and are highly expressed on Tregs, but show altered expression patterns at sites of inflammation. We aim to use molecular and cellular approaches to elucidate the roles of TIGIT and CD226 in primary human Treg function in health and disease.

Lead Investigators

• Dr Anne Pesenacker (Institute of Immunity & Transplantation, UCL)

Collaborators

• Professor Lucy Wedderburn (Institute of Child Health, UCL-GOS)
• Professor Adam Croft (Institute of Inflammation and Ageing, University of Birmingham)
• Professor David Sansom (Institute of Immunity & Transplantation, UCL)
• Professor Reza Motallebzadeh (Institute of Immunity & Transplantation, UCL)

Funding

• Versus Arthritis (Career Development Fellowship)
• Versus Arthritis (Bridging Fellowship)
• UCL-Birkbeck MRC DTP PhD Studentship

CD96 is a co-receptor which shares the ligand CD155(PVR) with TIGIT and CD226. We aim to investigate the hypothesis that CD96 regulation of CD155 modulates human Treg function. This work will involve a number of molecular and cellular approaches, including CRISPR-Cas9 gene editing, confocal microscopy, flow cytometry and mass spectrometry.

Lead Investigators

• Dr Anne Pesenacker (Institute of Immunity & Transplantation, UCL)

Collaborators

• Professor Konstantinos Thalassinos (Institute of Structural and Molecular Biology, UCL)
• Professor David Sansom (Institute of Immunity & Transplantation, UCL)

Funding

• UKRI BBSRC (New Investigator Research Grant)

Generation of T-cells occurs exclusively in the thymus dictating the immunological competence of its host. However, T-cell development is not constant throughout life. The thymus undergoes age-related involution that results in progressive deterioration of T-cell output, in addition to acute atrophy induced by multiple environmental stressors. We are investigating the fundamental mechanisms that underpin the involution process and establishing the contribution of thymic atrophy to age-related immune defects.

Lead Investigator

• Dr Jennifer Cowan (Institute of Immunity & Transplantation, UCL)

Collaborators

• Professor Benedict Seddon (Institute of Immunity & Transplantation, UCL)
• Dr Andreas Tiffeau-Mayer (Institute of Immunity & Transplantation, UCL)

Funding

• Wellcome Trust - Sir Henry Dale Fellowship

Antibodies produced by B cells have a diverse array of immunoglobulin variable regions mediating epitope specificities. Nine alternative immunoglobulin constant regions mediate differing effector functions of antibodies. Class switch recombination (CSR) is the mechanism that changes the antibody constant region and is crucial for immune homeostasis, effective immune responses to pathogens and development of protective vaccines. We aim to study how CSR efficacy is altered in systemic lupus erythematosus (SLE) patients, using in vitro models to determine underlying mechanisms involved.

Lead Investigators

• Professor Claudia Mauri (Institute of Immunity & Transplantation, UCL)

Collaborators

• Professor Deborah Dunn-Walters (University of Surrey, UK)
• Professor Franca Fraternali (Institute of Structural & Molecular Biology, UCL)
• Professor Christine Orengo (Division of Biosciences, UCL)
• Professor David Isenberg (Centre for Rheumatology, UCL Hospital)

Funding

• UKRI BBSRC (sLoLa scheme)
• LUPUS UK

Vaccines provide effective immunity against a wide range of pathogens. Most vaccines work in multiple doses to repeatedly stimulate B cells to produce protective antibodies. Critical for this process are germinal centres (GCs), which expand and select the highest quality B cells after each dose. We are investigating GC B cell interactions with follicular dendritic cells (FDCs), stromal cells that capture and display antigens to GC B cells. Understanding how FDCs retain antigens over time and how they stimulate B cells can improve vaccine design and simplify dosing.

Lead Investigators

• Professor Pavel Tolar (Institute of Immunity & Transplantation, UCL)

Collaborators

• Professor Shenshen Wang (University of California Los Angeles, USA)
• Professor Burkhard Ludewig (St Gallen, Switzerland)

Funding

• Medical Research Council

IgE antibodies have a key pathogenic role in allergy, but also provide protection against parasites, toxins, venoms, and even some types of cancers. We have shown that under normal conditions B cells that switch to IgE production are short-lived compared to other types of B cells and do not generate memory. We are investigating the underlying mechanism to provide insights into why sometimes the short-lived IgE response becomes chronic and drives allergy. This work aims to identify the immune defects that lead to excessive IgE production and develop approaches to counter this.

Lead Investigators

• Professor Pavel Tolar (Institute of Immunity & Transplantation, UCL)

Collaborators

• Professor Hannah Gould (King’s College London)
• Dr Faruk Ramadani (King’s College London)
• Professor Siobhan Burns (Institute of Immunity & Transplantation, UCL)

Funding

• Wellcome Trust

IgM is the archetypal antibody that governs B cell development and the initiation of the immune response to pathogens. We have determined the atomic structure of the IgM pentamer by cryogenic electron microscopy and identified the basis for its flexibility in binding to antigens. We are now using this knowledge to understand the structural basis for IgM interaction with effector molecules and cellular Fc-receptors. These studies open the way for IgM engineering and receptor targeting in disease.

Lead Investigators

• Professor Pavel Tolar (Institute of Immunity & Transplantation, UCL)

Collaborators

• Professor Peter Rosenthal (The Francis Crick Institute)

Funding

• The Francis Crick Institute