We investigate the mechanisms behind autoimmune diseases, such as Rheumatoid Arthritis, Systemic Lupus Erythematosus, diabetes and inflammatory bowel disease, and develop therapies to prevent them.
Disease Mechanisms in Autoimmunity
In autoimmunine diseases such as Rheumatoid Arthritis, Systemic Lupus Erythematosus, diabetes and inflammatory bowel disease, the immune system erroneously targets the body's own tissues.
By exploring genetic factors, environmental triggers, dysregulation of immune cell biology and intracellular signalling pathways, we aim to differentiate between protective and harmful immune responses.
Our research guides the creation of novel therapies and interventions essential for effectively controlling autoimmune conditions.
Projects
- Investigating the role of gut-barrier damage in patients with systemic autoimmunity
We have recently shown that there is increased gut leakiness and damage to the intestinal barrier in autoimmune conditions such as rheumatoid arthritis (RA). Furthermore, we have demonstrated that therapeutic restoration of gut permeability (pharmacologically or by dietry intervention) ameliorates joint inflammation. We now aim to identify what damages the specialised epithelial cells lining the gut in RA and systemic lupus erythematosus (SLE) to promote inflammation.
Lead Investigator
- Professor Claudia Mauri (Institute of Immunity & Transplantation, UCL)
Collaborators
- Dr Madhura Castellino (Division of Medicine ucl and ,UCL Hospital)
- Professor Franca Fraternali (Institute of Structural & Molecular Biology, UCL)
- Professor Antonio Uccelli (University of Genoa)
- Dr Alice Laroni (University of Genoa)
Funding
- Versus Arthritis
- Lorna and Yuti Chernajovsky Biomedical Research Foundation and Connect Immune Research
- Lupus UK
- Rosetrees Trust
- Regulatory B cell function in autoimmunity
Autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), affect approximately 10% of the UK population, impairing patient quality of life and generating a significant socioeconomic burden. The pathophysiology of most autoimmune diseases involves the generation of autoantibodies by an abnormal B cell compartment. We have shown that regulatory B cells (Bregs) are numerically and functionally reduced in SLE and RA, which may contribute to the chronic inflammation characteristic of these diseases. We aim to determine the signals driving the differentiation of Bregs under homeostatic conditions and how these are altered in autoimmunity, which has important translational implications.
Lead Investigators
- Professor Claudia Mauri (Institute of Immunity & Transplantation, UCL)
Collaborators
- Professor David A Isenberg (UCL Hospital, UK)
- Dr Madhura Castelino (University College London Hospital, UK)
- Professor Kai Kisand (University of Tartu, Estonia)
- Professor Claudio Mauro (University of Birmingham)
Funding
- Versus Arthritis
- Lupus UK
- Medical Research Council
- Rosetrees Trust
- Innovative Medicine Initiative (Horizon 2020)
- TPL-2 regulation of MAP kinase activation in inflammation
Toll-like receptor (TLR) activation of ERK1/2 mitogen-activated protein kinases (MAPKs) controls the expression of key cytokines in inflammation and is mediated via TPL-2, a MAP 3-kinase critical for innate immune responses to pathogens and genetically linked to the development of inflammatory bowel disease. We plan to use single cell techniques to measure ERK signal strength and dynamics to investigate how TLR stimulation activates the TPL-2 - ERK1/2 signalling pathway in macrophages. This fundamental information will be important in the development of TPL-2 inhibitors as anti-inflammatory medicines.
Lead Investigator
- Professor Steve Ley (Institute of Immunity & Transplantation, UCL)
Collaborators
- Dr Alix Le Marois (Francis Crick Institute)
- Dr Ralitsa Madsen (University of Dundee)
Funding
- Wellcome Trust
- TPL-2 regulation of immune responses to pathogenic bacteria
A key early step in innate immunity to pathogenic bacteria is the killing of phagocytosed bacteria by macrophages. This involves a process called phagosome maturation, in which internalised bacteria are trafficked into a series of increasingly acidified membrane-bound vacuoles and then degraded. We aim to investigate how TPL-2 kinase regulation of phagosome acidification in macrophages controls innate immune responses to pathogenic bacteria and the development of inflammatory bowel disease.
Lead Investigator
- Professor Steve Ley (Institute of Immunity & Transplantation, UCL)
Collaborators
- Dr Teresa Thurston (Imperial College London)
Funding
- Wellcome Trust
Treatment of Autoimmune Diseases
At the IIT, the goal of our research is to discover new ways to interfere with the immune responses that cause autoimmune diseases. Based on our findings, we are developing novel therapies to prevent or inhibit these conditions.
We are also using our insights to develop better strategies to predict the onset of disease and guide the selection of the best immunotherapies.
Projects
- Developing new Immunotherapies for Autoimmune Disease
Immune tolerance mechanisms prevent the development of autoimmune diseases. We are using mechanistic understanding of the pathways involved in immune tolerance to develop new immunotherapy approaches. Because common mechanisms underpin development of multiple autoimmune diseases, it may be possible to develop therapies that are effective in multiple conditions. Work in this area includes understanding how T cell activation thresholds are set by CTLA-4 and developing approaches that target regulatory T cells as well as pathogenic immune cell populations.
Lead Investigator
- Professor Lucy Walker (Institute of Immunity & Transplantation, UCL)
Co-Investigators
- Professor David Sansom (Institute of Immunity & Transplantation, UCL)
Collaborators
- Prof Vijay Chudasama (UCL Chemistry Department)
- Dr Sarah Teichmann (Wellcome Sanger Institute)
Funding
- Medical Research Council
- Diabetes UK
- Chernajovsky Foundation
- Checkpoint regulation of autoimmunity: mechanisms and predictive signatures
T cell responses are kept in check by regulatory pathways. Perturbation of these pathways during cancer immunotherapy can lead to autoimmune side-effects. We are exploring mechanisms and predictive signatures associated with checkpoint-inhibitor induced autoimmune tissue damage.
Lead Investigators
- Professor Lucy Walker (Institute of Immunity & Transplantation, UCL)
Collaborators
- Dr Amna Sheri (Consultant Medical Oncologist, Royal Free Hospital)
- Dr Alexander Pender (Consultant Medical Oncologist, Royal Free Hospital)
Funding
- Wellcome Trust
- CRUK
- Linking molecular characteristics to immune function in the CD28-CTLA-4 pathway
The CD28-CTLA-4 pathway represents an essential control point over T-cell responses, where loss of CTLA-4 function leads to autoimmunity and loss of CD28 compromises immunity. The CD28-CTLA-4 pathway is complex, classically involving two ligands (CD80 and CD86) both of which bind to CD28 and to CTLA-4. Different ligand affinities, dimerisation states as well as additional interactions with other pathways (e.g. PD-1- PD-L1) establish a complex series of positive and negative interactions that regulate T cell responses. This long term project aims to understand how the molecular characteristics of each component of the pathway regulate immune function in vitro and in vivo. We study these interactions at the biophysical, cellular and immune system levels and use mathematical approaches to predict how changes in ligand-receptor interactions can be used to manipulate immunity.
Lead Investigators
- Professor David Sansom (Institute of Immunity & Transplantation, UCL)
Co-Investigators
- Professor Lucy Walker (Institute of Immunity & Transplantation, UCL)
- Prof Dr Michael Meyer-Hermann (Helmholtz Centre for Infection Research)
- Dr Sahamoddin Khailaie (Helmholtz Centre for Infection Research)
Collaborators
- Professor Dane Wittrup (Massachusetts Institute of Technology)
- Dr Gosia Trynka (Wellcome Trust Sanger Institute)
- Dr Shinji Ikemizu (Kumamoto University)
Funding
- Wellcome Trust
- CRISPR Screening of T cell Costimulation and CTLA-4 transendocytosis
CTLA-4 suppresses T cell responses by controlling the expression of CD28 ligands using a process known as transendocytosis. Here the two CD28 ligands CD80 and CD86 are removed from antigen presenting cells thereby restricting CD28 costimulation. Neither the molecular mechanism of transendocytosis nor the signalling pathway of CD28 are fully understood. In collaboration with the Sanger Institute, we are using CRISPR/Cas9 approaches to screen for genes required for transendocytosis and for CD28 costimulation. Both projects aim to identify useful new targets for immune regulation.
Lead Investigators
- Professor David Sansom (Institute of Immunity & Transplantation, UCL)
Collaborators
- Dr Gosia Trynka (Wellcome Trust Sanger Institute)
- Dr Blagoje Soskic (Human Technopole Milan)
- Dr Anneliese Speak (University of Cambridge)
Funding
- Wellcome Trust
- The Wellcome Trust Sanger Institute
- Open Targets
- Investigating how ligand and antibody affinity and dimerisation affect the fate of CTLA-4
CTLA-4 captures and destroy its ligands (CD80 and CD86) using a process known as Transendocytosis (TE). This involves intracellular delivery of CTLA-4 to immune contacts (between T cells and antigen presenting cells) followed by rapid internalisation of the ligand from opposing cells with either recycling or degradation of CTLA-4 depending on the bound ligand. CD80 is a homodimer whilst CD86 is a monomer, raising the possibility that such differences may influence CTLA-4 fate. CD80 also directly interacts with PD-L1, generating a CD80-PD-L1 heterodimer. As a result, CTLA-4 may interact with at least 3 different ligand species; a CD80 homodimer, CD80-PD-L1 heterodimer and a CD86 monomer all of which may affect its fate. Similarly whilst, therapeutic antibodies traditionally have high affinity bivalent interactions, increasingly bispecific and other designs are increasingly being utilised, allowing us to test the impact of valency (e.g. bivalent vs. monovalent) and structure/geometry of antibody interactions on CTLA-4 biology.
Lead Investigators
- Professor David Sansom (Institute of Immunity & Transplantation, UCL)
Collaborators
- Dr. Simon Dovedi (Astra Zeneca)
Funding
- Medical Research Council iCASE studentship (with AstraZeneca)
- Mass Spectrometry analysis of the CTLA-4 interactome
The proteins regulating the cell biology of CTLA-4 remain largely undefined. We are studying the CTLA-4 interactome using using immunoprecipitation and mass spectrometry approaches to define key interactions involved in CTLA-4 function.
Lead Investigators
- Professor David Sansom (Institute of Immunity & Transplantation, UCL)
Collaborators
- Dr. Roger Geiger (IRB Bellinzona)
Funding
- Wellcome Trust
- Analysis of CTLA-4 mutations in Immunodeficiency
Genetic mutations in CTLA-4 occur in a rare group of patients who suffer from a variable immune dysregulation syndrome. A number of different mutations have been identified and we have studied many of these to understand more about CTLA-4 function. We are mapping the functional changes that occur with such mutations, studying their expression, affinity changes, ligand interaction and transendocytosis phenotypes. These studies provide useful information on structure-function relationships and approaches to identifying functionally significant variants for diagnostics.
Lead Investigators
- Professor David Sansom (Institute of Immunity & Transplantation, UCL)
Collaborators
- Professor Siobhan Burns (Institute of Immunity & Transplantation, UCL)
- Professor Emma Morris (Institute of Immunity & Transplantation, UCL)
- Professor Bodo Grimbacher (University of Freiberg)
- Dr Gulbu Uzel (National Institutes of Health)
- Professor Sophie Hambleton (University of Newcastle)
Funding
- Wellcome Trust
- Gene engineered T cells as live medicines
T cells play a critical role in human health. Effector T cells can protect against cancer and prevent viral infection, while regulatory T cells can avoid the development of autoimmune diseases such as multiple sclerosis and type 1 diabetes. We use gene transfer and gene editing technologies to produce effector T cells that can selectively attack cancer cells, and to produce disease-specific regulatory T cells switch off pathogenic T cells in the tissue affected by autoimmunity, but not elsewhere in the body. Engineered T cells can be used as live medicines for the treatment of cancer and autoimmune conditions.
Lead Investigator
- Professor Hans Stauss (Institute of Immunity & Transplantation, UCL)
Funding
- Apollo Therapeutics
- Wellcome Trust
- UKRI
- EU T2Evolve Consortium
- Turkish Ministry of Education
- Thailand Ministry of Education
Our experts
Prof. Claudia Mauri
Immunology
Prof. Steve Ley
Chair, Molecular Immunology
Prof. Lucy Walker
Chair, Immune Regulation
Prof. David Sansom
Chair, Transplant Immunology
Prof. Hans Stauss
Tumour Immunology
Selected Publications
- Herold KC, Delong T, Perdigoto AL, Biru N, Brusko TM, Walker LSK (2024). The immunology of type 1 diabetes. Nat Rev Immunol. 2024 Jun;24(6): 435-451.
- Bradford HF, McDonnell TCR, Stewart A, Skelton A ... Mauri C (2024). Thioredoxin is a metabolic rheostat controlling regulatory B cells. Nat Immunol. 2024 May;25(5): 873-885.
- Degirmencay A, Thomas S, Holler A, Burgess S, Morris EC, Stauss HJ (2024). Exploitation of CD3ζ to enhance TCR expression levels and antigen-specific T cell function. Front Immunol. 2024 May 30;15: 1386132.
- Degirmencay A, Thomas S, Mohammed F, Willcox BE, Stauss HJ (2023). Modifications outside CDR1, 2 and 3 of the TCR variable β domain increase TCR expression and antigen-specific function. Front Immunol. 2023 Apr 12;14: 1148890.
- Kennedy A, Robinson MA, Hinze C, Waters E, Williams C, Halliday N, Dovedi S, Sansom DM (2023). The CTLA-4 immune checkpoint protein regulates PD-L1:PD-1 interaction via transendocytosis of its ligand CD80. EMBO J. 2023 Mar 1;42(5): e111556.
- Bradford HF, Haljasmägi L, Menon M, McDonnell TCR ... Mauri C (2023). Inactive disease in patients with lupus is linked to autoantibodies to type I interferons that normalize blood IFNα and B cell subsets. Cell Rep Med. 2023 Jan 17;4(1): 100894.
- Wang CJ, Petersone L, Edner NM ... Walker LSK (2022). Costimulation blockade in combination with IL-2 permits regulatory T cell sparing immunomodulation that inhibits autoimmunity. Nat Commun. 2022 Nov 9;13(1): 6757.
- McGovern J, Holler A, Thomas S, Stauss HJ (2022). Forced Fox-P3 expression can improve the safety and antigen-specific function of engineered regulatory T cells. J Autoimmun. 2022 Oct;132: 102888.
- Kennedy A, Waters E, Rowshanravan B ... Walker LSK, Sansom DM (2022). Differences in CD80 and CD86 transendocytosis reveal CD86 as a key target for CTLA-4 immune regulation. Nat Immunol. 2022 Sep;23(9): 1365-1378.
- Williams C, Kennedy A, Robinson MA, Lloyd C, Dovedi SJ, Sansom DM (2022). Impact of CTLA-4 checkpoint antibodies on ligand binding and Transendocytosis. Front Immunol. 2022 Aug 31;13: 871802.
- Blair L, Pattison MJ, Chakravarty P, Papoutsopoulou S, Bakiri L, Wagner EF, Smale S, Ley SC (2022). TPL-2 Inhibits IFN-β Expression via an ERK1/2-TCF-FOS Axis in TLR4-Stimulated Macrophages. J Immunol. 2022 Feb 15;208(4): 941-954.
- Matei DE, Menon M, Alber DG, Smith AM ... Mauri C (2021). Intestinal barrier dysfunction plays an integral role in arthritis pathology and can be targeted to ameliorate disease. Med. 2021 Jul 9;2(7): 864-883.e9.
- Breyer F, Härtlova A, Thurston T, Flynn HR ... Ley SC (2021). TPL-2 kinase induces phagosome acidification to promote macrophage killing of bacteria. EMBO J. 2021 May 17;40(10): e106188.
- Edner NM, Heuts F, Thomas N ... Walker LSK (2020). Follicular helper T cell profiles predict response to costimulation blockade in type 1 diabetes. Nat Immunol. 2020 Oct;21(10): 1244-1255.
- Rosser EC, Piper CJM, Matei DE, Blair PA ... Mauri C (2020). Microbiota-Derived Metabolites Suppress Arthritis by Amplifying Aryl-Hydrocarbon Receptor Activation in Regulatory B Cells. Cell Metab. 2020 Apr 7;31(4): 837-851.e10.
- Ovcinnikovs V, Ross EM, Petersone L ... Sansom DM, Walker LSK (2019). CTLA-4-mediated transendocytosis of costimulatory molecules primarily targets migratory dendritic cells. Sci Immunol. 2019 May 31;4(35): eaaw0902.
- Thomas S, Mohammed F, Reijmers RM, Woolston A ... Stauss HJ (2019). Framework engineering to produce dominant T cell receptors with enhanced antigen-specific function. Nat Commun. 2019 Oct 1;10(1): 4451.
- Ventura S, Cano F, Kannan Y, Breyer F, Pattison MJ, Wilson MS, Ley SC (2018). A20-binding inhibitor of NF-κB (ABIN) 2 negatively regulates allergic airway inflammation. J Exp Med. 2018 Nov 5;215(11): 2737-2747.