PhD projects and supervisors

Learn about potential supervisors, their research interests, and potential PhD projects for postgraduate research within the Division of Infection and Immunity.

Professor Paola Bonfanti

Epithelial Cell biology and Regenerative Medicine Lab

Our research group aims to understand how epithelial organs such as thymus, oesophagus and airways develop, change with aging, and become susceptible to diseases. The lab is currently based at the Francis Crick Institute and projects make use of facilities at UCL and Crick institutes.

Our research program focuses on epithelial cell biology and immunology. We aim to uncover the mechanisms behind tissue and organ regeneration, as well as the intricacies of disease processes. In the lab, we leverage a diverse array of cutting-edge technologies, such as stem cell biology, microfluidics, next-generation sequencing, and molecular analysis. Our multidisciplinary approach integrates these advanced technologies with innovative translational methods to tackle unmet clinical needs.

Paola Bonfanti: UCL Profile

PhD projects - Paola Bonfanti

Potential PhD projects will have the opportunity to engage in fundamental questions in human thymus biology and T cell development. The projects will explore immune tolerance and contribute to the development of translational approaches for both congenital and chronic disorders, including cancer. Our dynamic and collaborative environment fosters scientific innovation and provides a solid foundation for training junior researchers.

Relevant publications

1. Savvidis et al. Advanced three-dimensional X-ray imaging unravels structural development of the human thymus compartments. 2024 Communications Medicine.
2. Reuschl et al. Enhanced innate immune suppression by SARS-CoV-2 Omicron subvariants. Nature Microbiology 2024
3. Ragazzini et al. Defining the identity and the niches of epithelial stem cells with highly pleiotropic multilineage potency in the human postnatal thymus. Developmental Cell 2023
4. Bouhaddou, Reuschl et al. SARS-CoV-2 variants evolve convergent strategies to remodel the host response. Cell 2023
5. Mesner, Reuschl et al. SARS-CoV-2 evolution influences GBP and IFITM sensitivity. Proceedings National Academic of Science 2023 120 (5) e2212577120.
6. Watson et al. Integrated Role of Human Thymic Stromal Cells in Hematopoietic Stem Cell Extravasation. Bioengineering and Translational Medicine 2023 Mar; 8(2): e10454 
7. Campinoti, Gjinovci, Ragazzini et al. Reconstitution of a functional human thymus by postnatal progenitor cells and natural whole organ scaffolds. Nature Communications 2020
8. Claudinot et al. Beyond Lineage Restriction: Tp63-Expressing Adult Epithelial Stem Cells Have Latent Hairy Skin Competence. Nature Communications 2020 Nov 6;11(1): 5645.
9. Park et al. A cell atlas of human thymic development defines T cell repertoire formation. Science 2020, 21;367 (6480).
10. Giobbe et al. Extracellular matrix hydrogel derived from decellularized tissues enables endoderm organoids culture. Nature Communications 2019 Dec 11;10(1): 5658.
11. Bonfanti et al. “Hearts and Bones”: The Ups and Downs of “Plasticity” in Stem Cell Biology. EMBO Molecular Medicine. 2012 May;4(5): 353-61. Review 
12. Bonfanti et al. Microenvironmental Reprogramming of Thymic Epithelial Cells to Skin Multipotent Stem Cells. Nature. 2010 Aug 19;466(7309): 978-82

Professor Benny Chain

Reading and understanding the T cell repertoire

The adaptive immune system is based on a unique molecular system which generates an enormous diversity of receptors on T and B lymphocytes, each with the potential to recognise a different molecular pattern, and hence stimulate a specific immune response to a particular pathogen. The size of the receptor diversity in every individual is estimated to be in the order of 1009-1010 different receptors. With the advent of massively parallel high throughput sequencing, it has now become possible to analyse this repertoire directly, and we have developed a new quantitative pipeline exploiting this technology for T cell receptor repertoire studies. This data has the potential to shed light on basic immunological paradigms, providing quantitative data on clone size, clone diversity and kinetics during immune responses which will be a key step in our long term objective of building multi-level mathematical models of immune system function. It also has enormous potential in more applied applications, such as diagnosis of infectious disease, cancer and autoimmunity.

Benny Chain: UCL Profile

PhD projects - Benny Chain

Potential PhD projects combine wet lab and computational training opportunities. The experimental data use high throughput sequencing to analyse repertoires from a range of clinical sample collections, which include samples from individuals with infectious disease (tuberculosis, HIV and COVID-19), autoimmunity, immunodeficiency, transplantation or cancer. Computational analysis focuses on developing ways to interrogate this data to understand the underlying biology. Specifically we develop methods to compare different TCR sequences, and cluster them in ways which reflect their functional antigen specificity. The goal is to be able to predict the peptide specificity of a T cell receptor from its sequence alone. We are collaborating with Prof. John Shawe-Taylor to apply recent advances in machine learning to protein sequence analysis.

The projects will provide training in immunology, molecular biology and computational biology. The projects will therefore be positioned at the intersection between machine learning and high throughput genomic technologies, which is one of the fastest moving and most exciting areas of the biomedical sciences.

Relevant publications

1.    Nagano, Yuta, et al. "Contrastive learning of T cell receptor representations." arXiv preprint arXiv:2406.06397 (2024).
2.    Milighetti et al.  Large clones of pre-existing T cells drive early immunity against SARS-COV-2 and LCMV infection. iScience. 2023 Jun 16;26(6): 106937.
3.    Joshi K, Milighetti M, Chain BM. Application of T cell receptor (TCR) repertoire analysis for the advancement of cancer immunotherapy. Curr Opin Immunol. 2022 Feb;74: 1-8.

Dr Jennifer Cowan

Controlling thymus function to improve T-cell immunity in the aged

T-cells play essential roles in immune responses. Dysregulated T-cell development or maintenance results in diverse immunologically mediated diseases ranging from immunodeficiency to autoimmunity. The generation of T-cells occurs exclusively in the thymus, thus, this organ dictates the immunological competence of the host.

However, T-cell development is not constant throughout life, and the thymus undergoes age-related involution that results in progressive deterioration of T-cell output, in addition to acute atrophy under multiple stressors. The consequences of this chronic and acute reductions in thymus function on the establishment and maintenance of different T-cell subsets remains unclear, along with its impact on underlying age-related immune defects. This is due to the limitation in models allowing efficient prevention or reversal of thymic involution in old age.

Jennifer Cowan: UCL Profile

PhD projects - Jennifer Cowan

In the lab we have generated mouse models in which thymic involution can be reversed in aged mice. As a PhD student you would explore how rejuvenating thymic function alters T-cell subsets within the secondary lymphoid organs and in tissues, following immunological challenge. This will involve flow cytometric phenotyping of different T-cell subsets in multiple tissues and the analysis of single cell RNA sequencing data sets and TCR repertoire analysis. This approach will enable the identification of effector T-cells in older mice with restored thymic function, compared to aged controls and explore differences in their function, transcriptional profiles and repertoire. Overall, the project will explore the effects of aging on T-cells and identify what age-associated changes to T-cells are a consequence of thymic involution.

Relevant publications

1. Cowan JE et al, Postnatal Involution and Counter-Involution of the Thymus. Frontiers in Immunology. 2020 May 12.
2. Cowan JE et al. Myc Controls A Distinct Transcriptional Program in Fetal Thymic Epithelial Cells That Determines Thymus Growth, Nature Communications. 2019 Dec 02.
3. Rane S et al. Age is not just a number: Naive T cells increase their ability to persist in the circulation over time. PLoS Biol. 2018 Apr 11.

Professor Ariberto Fassati

Project areas: HIV-1 latency and Transmissible cancers

We study two pathogens that have a remarkable ability to evade the immune system, namely HIV-1 and the canine transmissible venereal tumour (CTVT). To cure HIV-1 infection, it is essential to eliminate the latent viral reservoir, either by purging infected cells or inducing a state of super-latency that mirrors the repression of endogenous retroviruses in our genome. To develop effective HIV-1 cure strategies, we have integrated chemical biology and "omics" approaches to understand the mechanisms controlling HIV-1 latency and how drugs may influence it. For instance, we discovered that Hsp90 is a druggable regulator of HIV-1 latency, and that the hormone receptor RORC2 is vital for HIV-1 reactivation from latency. We also found that the cardiac glycoside digoxin inhibits HIV-1 gene expression in a manner dependent on the genomic region where the virus has integrated. This finding suggests that HIV-1 preferentially integrates into clusters of co-regulated genes, potentially affecting virus latency. 

Ariberto Fassari: UCL Profile

PhD projects - Ariberto Fassati

Project 1: To test the above hypothesis, we are examining how the 3D organization of chromatin, where HIV-1 integrates, influences the virus's ability to enter or exit latency. We have optimized chromosomal conformation capture techniques (HiC) to study changes in chromatin 3D organization upon CD4 T cell activation, along with identifying unique HIV-1 integration sites. We hypothesize that clusters of integration sites located in dynamic 3D chromatin regions represent likely hotspots for reversible latency. These hotspots could be potential targets for selective epigenetic modifiers.

Project 2: Some years ago, we demonstrated that CTVT transmits itself as a cellular parasite. CTVT evades allorecognition during transmission, regardless of the dog's leukocyte antigen type. Nevertheless, it can be rejected by the immune system when the drug vincristine is administered. This extreme bi-modal phenotype is particularly fascinating, as it may provide insights into preventing transplant rejection and triggering the rejection of human cancers. We discovered that vincristine induces CTVT rejection by activating the innate immune system. To understand how a cancer can become transmissible, we have passaged a mouse melanoma in progressively immunologically mismatched mouse strains and obtained an allo-transplantable cancer model. We are using transcriptomics and genomic to study the evolution of this transplantable cancer and the mechanisms that render it able to escape allogeneic rejection.

Relevant publication

1. Tomas Raul Wiche Salinas, Yuwei Zhang, Daniele Sarnello, Alexander Zhyvoloup, et al. Th17 cell master transcription factor RORC2 regulates HIV-1 gene expression and viral outgrowth. Proc Natl Acad Sci U S A. 2021; 118(48) e2105927118.
2. Zhyvoloup A, Melamed A, Anderson I, Planas D, Lee CH, Kriston-Vizi J, Ketteler R, Merritt A, Routy JP, Ancuta P, Bangham CRM, and Fassati A. Digoxin reveals a functional connection between HIV-1 integration preference and T-cell activation. PLoS Pathog. 2017 Jul 20;13(7).
3. Anderson I, Low JS, Weston S, Weinberger M, Zhyvoloup A, Labokha AA, Corazza G, Kitson RA, Moody CJ, Marcello A, Fassati A. Heat shock protein 90 controls HIV-1 reactivation from latency. Proc Natl Acad Sci U S A. 2014 Ap 15;111(15): e1528-37.
4. Murgia C, Pritchard JK, Kim SY, Fassati A, Weiss RA. Clonal origin and evolution of a transmissible cancer. Cell. 2006;126(3): 477-87.
5. Frampton D, Schwenzer H, Marino G, Butcher LM, Pollara G, Kriston-Vizi J,..and Fassati, A. Molecular Signatures of Regression of the Canine Transmissible Venereal Tumor. Cancer Cell. 2018;33(4): 620-33 e6.

Professor Richard Goldstein

Decoding the evolutionary record: What advanced models of sequence change can reveal about DNA, genes, and gene products

Nature has been performing ultra-high throughput in vivo site-directed mutagenesis studies for the past few billion years. The resulting evolutionary record contains a wealth of information about proteins, their structure, function, and physiological context, and how proteins adapt to changing circumstances. Unfortunately, standard phenomenological models used to analyse sequence change generally assume the effects we are most interested in - the variations of selection between different locations and at different times - do not exist. By constructing more mechanistic models that explicitly consider the process of mutation and selection we can decipher the resulting patterns of sequence variation and conservation, providing us access to Nature's lab notebook. We use these models to represent the nature of the selective constraints acting on protein sequences, to examine how protein sequences in influenza adapt to changes of host, and to characterize the effect of mutations on proteins - what proportions are deleterious, neutral, advantageous - an important distribution for modelling of population genetics.

Richard Goldstein: UCL Profile

PhD projects - Richard Goldstein

Project: The analysis of selection on non-coding regions

Our entire genome, as well as that of all pathogens, is shaped by the process of molecular evolution. In particular, the nucleotide bases and amino acids found in different locations are sculpted by the constraints at those locations, constraints that arise from the function, structure, physiological role, and context at that site. Some important locations must preserve some important property such as size, charge, or hydrogen bonding location. Other locations need to change as the constraints on that site change due to, for instance, a change in function or a change in host. Still other locations in pathogen genomes or immune system genes need to change rapidly so as to avoid causing an effective immune response, or to respond to the changing pathogens. A number of standard approaches have been developed to analysing the strength and nature of the selection (and changes in the selection) in protein-coding genes - one of the most common is to compare the rate of nucleotide substitutions that do or do not result in amino acid changes. These and other methods do not work well in non-coding regions, where there is no amino acid to change. Yet much of the interesting evolutionary dynamics involves changes in non-coding regions such as promoters. There has been increased interest in other non-coding regions as well, including where various RNA molecules are transcribed but not translated into proteins. There is also much interest in the non-coding regions of 'selfish elements' in the genomes such as endogenous retroviruses and other transposable elements. This project would involve developing computational approaches to analyse selection acting on non-coding parts of the genome, including adapting these methods to the study of transposable elements in the genome, and how they are regulated by the host in which they reside.

Relevant publications

1. Benjamin P. Blackburne, Alan J. Hay, and Richard A. Goldstein (2008), Changing patterns of selective pressure in Human Influenza H3, PLoS Pathogens, 4, e1000058, PMID: 18451985. 
2. Mario dos Reis, Alan J. Hay, and Richard A. Goldstein (2009), Using Non-Homogeneous Models of Nucleotide Substitution to Identify Host Shift Events: Application to the Origin of the 1918 ‘Spanish’ Influenza Pandemic Virus, J Mol Evol., 69 ,333-345, PMID: 19787384.
3. Asif U. Tamuri, Mario dos Reis, Alan J. Hay, Richard A. Goldstein (2009). Identifying changes in selective constraints: Host shifts in influenza. PLoS Comput Biol., 5, e1000564, PMID: 19911053.
4. Mario dos Reis, Asif U. Tamuri, Alan J. Hay, Richard A. Goldstein (2011). Charting the host adaptation of influenza viruses. Mol Biol Evol 28:1755-1767, PMID: 21109586.
5. Asif U. Tamuri, Mario dos Reis, Richard A. Goldstein (2012). Estimating the distribution of selection coefficients from phylogenetic data using sitewise mutation-selection models, Genetics, 190:1101-1115, PMID: 22209901.

Professor Clare Jolly

My lab seeks to understand what makes a cell permissive for virus infection. Specifically, we focus on HIV manipulates T cells to support viral replication and spread, and the consequences of this for the virus and the host. We are also applying our expertise in viral cell biology to dissect mechanisms of SARS-CoV-2 replication and spread between cells, and adaptation to humans, with emphasis on innate immunity. Cell-to-cell spread is the dominant mode of HIV dissemination and takes place at immune cell contacts called virological synapses (VS). This confers a many of advantages for the virus including rapid infection of target cells, evasion of components of the innate and adaptive immunity and increased resistance to some antiretrovirals. Therefore cell-cell spread poses a considerable barrier to eradicating HIV from infected individuals.

We seek to understand how this process works at the molecular level and to exploit cell-cell spread to uncover new biology about HIV. For example, we have recently discovered that cell-cell spread at the VS drives CD4+ T cells to become permissive to HIV infection. This is exciting as it provides a new paradigm for why cell-cell spread is so efficient – the virus changes T cells to make them better able to support replication. We are now asking how cell-cell spread triggers T cell permissivity, how this influences antiviral defences and what viral and cellular determinants regulate these processes. We have also shown that cell-cell spread of HIV reprograms CD4 T cells in a unique way that means these cells are more likely to hide in tissues to form viral reservoirs and we are now working to understand mechanism and implications for pathogenesis.

We use a range of experimental techniques and approaches including (but not limited to) tissue culture, virological and immunological assays, molecular biology, mutagenesis and genetic manipulation of viruses and cells, advanced imaging approaches and multicolour flow cytometry.

Clare Jolly: UCL Profile

PhD projects - Clare Jolly

PhD projects are available to work on any aspect of the above areas of research on HIV and SARS-CoV-2. My lab currently consists of 5 post-doctoral scientists and 1 PhD student and is funded by the Wellcome Trust and a collaborative NIH grant. We regularly host MSc and iBSc project students and are an interactive lab that collaborates with many other groups around UCL and beyond.

Relevant publications

1. Reuschl A.K.,Thorne L.G.,Whelan M.V.X.,Ragazzini R.,Furnon W.,Cowton V.M.,De Lorenzo G.,Mesner D.,Turner J.L.E.,Dowgier G… Jolly C* and Towers G.J. (2024) Evolution of enhanced innate immune suppression by SARS-CoV-2 Omicron subvariants. Nature Microbiology 9 (2) 451-463 PMC10847042.
2. Bouhaddou M.,Reuschl A.K.,Polacco B.J.,Thorne L.G.,Ummadi M.R.,Ye C.,Rosales R.,Pelin A.,Batra J.,Jang G.M…. Jolly C*., Towers G.J. and Krogan N.J. (2023) SARS-CoV-2 variants evolve convergent strategies to remodel the host response. Cell 186, 4597-614 e26. PMC10604369.
3. Thorne L.G.,Bouhaddou M.,Reuschl A.K.,Zuliani-Alvarez L.,Polacco B.,Pelin A.,Batra J.,Whelan M.V.X.,Hosmillo M.,Fossati A…..Jolly C*. Towers G.J. and Krogan N.J. (2022)  Evolution of enhanced innate immune evasion by SARS-CoV-2. Nature 602, 487-95. PMC8850198.
4. Reuschl A-K., Shivkumar M., Mesner D., Pallett L.J., Guerra-Assuncao-J.A., Mandansein R., Dullabh K.J., Sigal A., Thornhill J.P., Herrera C., Fidler S., Noursadeghi M., Maini M.K and Jolly C*. (2022) HIV-1 Vpr drives a tissue residency-like phenotype during selective infection of resting memory T cells. Cell Reports 39(2) PMC9350556.
5. Mesner D. et al., (2020) Loss of Nef-mediated CD3 down-regulation in the HIV-1 lineage increases viral infectivity and spread, Proc Natl Acad Sci USA 117: 7382-7391. PMC7132320.

Professor Steve Ley

Following infection, pathogenic bacteria trigger defensive Toll-like receptors (TLRs) on macrophages to activate mitogenactivated protein kinases (MAPKs), which control the expression of cytokines and chemokines that are essential for development of immunity to pathogens. TLR activation of the ERK1/2 and p38a MAP kinases in macrophages is mediated via Tumour Progression Locus 2 (TPL-2; MAP3K8), a MAP 3-kinase. TPL-2 is critical for inflammatory immune responses to bacteria, fungi and viruses (Gantke; Pattison. See refs 1, 2, below.)

My laboratory has previously identified two critical steps in TPL-2 activation that are directly controlled by IkB kinase (IKK), revealing a direct link between the activation of ERK1/2 MAP kinases and NF-kB transcription factors in innate immune responses (Arthur. See ref. 3 below.)

Steve Ley: UCL Profile

PhD projects - Steve Ley

TPL-2 regulation of innate immune responses to pathogenic bacteria

A key early step in innate immune responses 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  embrane-bound vacuoles and then degraded. Recent research by the Ley laboratory has shown that TPL-2 complex stimulates phagosome maturation independently of its established functions in MAP kinase activation (ref 4, below). One PhD project will investigate the importance of this newly discovered regulatory process in innate immune responses to the pathogenic bacteria.

Employing in vitro and in vivo model systems, this will focus on two pathogenic bacterial species :

• Staphylococcus aureus, an extracellular Gram-positive bacterium that is the common cause of pneumonia and the pathogen most frequently linked to health care associated pneumonia.
• Salmonella typhimurium, a Gram-negative pathogen that causes both gastrointestinal and systemic diseases.

TPL-2 regulation of cell survival following HCMV infection

Viruses have proven excellent tools to probe signalling pathways regulating key aspects of cell biology. Our unpublished data suggests that human cytomegalovirus (HCMV) activates TPL-2- ERK1/2 MAP kinase signalling pathway to establish latency in myeloid cells. In collaboration with the Matthew Reeves laboratory, one PhD project will investigate the mechanisms by which HCMV stimulates plasma membrane and endosomal TLR receptors to activate TPL-2 and the downstream consequences of TPL-2 signalling for HCMV infection.

Relevant publications

1. Gantke T, Sriskantharajah S, Sadowski M, Ley SC. IκB kinase regulation of the TPL-2/ERK MAPK pathway. Immunol Rev. 2012;246:168 - 82.
2. Pattison MJ, Mitchell O, Flynn HR, Chen C-S, Yang H-T, Ben-Addi A, et al. TLR and TNFR1 activation of the MKK3/MKK6- p38alpha axis in macrophages is mediated by TPL-2 kinase. Biochem J. 2016;473:2845 - 61.
3. Arthur JSC, Ley SC. Mitogen-activated protein kinases in innate immunity. Nature Rev Immunol. 2013;13:679 - 92.
4. Breyer F, Hartlova A, Thurston T, Flynn HR, Chakravarty P, Janzen J, et al. TPL-2 kinase induces phagosome acidification to promote macrophage killing of bacteria. EMBO J. 2021;40:e106188.

Professor Mala Maini

I am Professor of Viral Immunology based in the UCL Institute of Immunity and Transplantation, and Honorary Consultant Physician in the viral hepatitis clinic within CNWL NHS Foundation Trust. My research has always been closely informed by the patients I see in my clinics and the samples they generously donate through our network of clinical collaborators. Research in the Maini Lab is funded by the Wellcome Trust, Cancer Research UK, ERC Horizon 2020 and UKRI.

My lab studies adaptive immunity to hepatitis B, liver cancer and SARS-CoV-2 to inform the development of immunotherapies and vaccines for these major causes of morbidity and mortality. We focus on the regulation and harnessing of tissue-resident immunity for frontline sentinel surveillance of viruses and cancer. Through access to well-characterised patient cohorts, human tissue samples and in vitro and in vivo models, our studies provide insights into beneficial and dysfunctional T and B cell responses. The lab is particularly interested in the tolerogenic features of liver immunity, focusing on cellular interactions and metabolic constraints to develop novel immunotherapeutic strategies for hepatic pathogens and tumours.

Our team is an enthusiastic, sociable and committed group of basic and clinical scientists. We have a great track record with PhD students, who have a well-supported and enjoyable time in our group, whilst publishing highly impactful studies. 

Mala Maini: UCL Profile

PhD projects - Mala Maini

If you join our lab you will have your own project on a topical aspect of hepatitis B, liver cancer or SARS-CoV-2 that will interlink with those of the other team members for maximum productivity. We are highly interactive, working closely with staff in a number of clinics to obtain the patient samples so vital to our translational work, as well as with scientific collaborators and a network of consortia here at UCL and internationally.

I have a strong commitment to mentoring and supporting my lab members to obtain fellowships and develop their careers, several of whom now run their own labs alongside mine, with the wonderful help of our lab manager and joint team of technicians.

Relevant publications

1. Pallett L.J, Swadling L., Diniz M ... Maini M.K. Tissue CD14+CD8+T-cells are reprogrammed by myeloid cells and modulated by LPS. Nature. 2023 Feb; 614: 334-342
2. Diniz MO, Mitsi E, Swadling L ... Ferreira D*, Maini MK*. Airway-resident T cells from unexposed individuals cross-recognize SARS-CoV-2. Nature Immunol. 2022 Sep;23(9): 1324-1329. *Joint senior authors
3. Diniz MO, Schurich A, Chinnakannan SK ... Maini MK. NK cells limit therapeutic vaccine-induced CD8+T cell immunity in a PD-L1-dependent manner. Science Translational Medicine 2022 Apr13;14(640): eabi4670
4. Swadling L, Diniz MO, Schmidt NM ... Maini MK. Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2. Nature 2022 Jan;601(7891): 110-117
5. Burton AR, Pallett LJ, McCoy LE ... Pelletier N, Maini MK. Circulating and intrahepatic antiviral B cells are defective in hepatitis B Journal of Clinical Investigation 2018 Oct 1;128(10): 4588-4603.

Professor Claudia Mauri

We are a very dynamic and culturally diverse group, whom research focuses on delineating the cellular and molecular mechanisms controlling immune-regulation in health and how these pathways are dysregulated in autoimmune disease. We have pioneered the discovery of a novel subset of B-cells, known as regulatory B-cells (Bregs), which possess powerful immune-suppressive capacity. 

Our studies have overturned the pre-existing paradigm of B-cells being exclusively pathogenic in autoimmunity. In mice and humans, we have demonstrated that Bregs can directly suppress pro-inflammatory cytokine production by, and proliferation of, naïve, memory, and auto-reactive T-cells, whilst supporting the differentiation of regulatory T-cells via the release of IL-10.

In autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) and, Bregs have lost their capacity to suppress pro-inflammatory T-cell responses and fail to control inflammation. By studying Breg function in healthy versus disease, we discovered for the first time that B-cells and Bregs present lipid-antigen to iNKT-cells via CD1d, that in healthy individuals iNKT-cells are converted into immunoregulatory iNKT-cells in response to Breg lipid presentation, but that in SLE defects in B-cell CD1d recirculation lead to altered lipid presentation, and reduced number and suppressive capacity of iNKT-cells.

More recently, our research has uncovered the signals that drive and regulate Breg development and activation and has unravelled an important role for gut microbiota in the differentiation of Bregs and plasma cells producing antibody and identified novel gut-derived metabolites that alter systemic inflammatory processes.

Claudia Mauri: UCL Profile

PhD projects - Claudia Mauri

The projects available will aim to investigate:

1. The effect that diet and/or dietary components have on the metabolism of B cells
2. How changes in the gut-microbiota can be harness for the cure of rheumatoid arthritis.

Relevant publications

1. Bradford HF, Mauri C. Diversity of regulatory B cells: Markers and functions. Eur J Immunol. 2024 Jul 31:e2350496. doi: 10.1002/eji.202350496.
2. Rosser EC, Mauri C. The emerging field of regulatory B cell immunometabolism. Cell Metab. 2021 Jun 1;33(6):1088-1097. doi: 10.1016/j.cmet.2021.05.008.
3. Oleinika K, Rosser EC, Matei DE, Nistala K, Bosma A, Drozdov I, Mauri C. CD1d-dependent immune suppression mediated by regulatory B cells through modulations of iNKT cells. Nat Commun. 2018 Feb 15;9(1):684. doi: 10.1038/s41467-018-02911-y.

Professor Mahdad Noursadeghi

We investigate host-pathogen interactions in order to increase our mechanistic understanding of protective and pathogenic immune responses in infectious diseases, and inform the development of novel therapies or approaches for patient stratification. We particularly focus on innate immunity by modelling host-pathogen interactions in human macrophages.

Although macrophages are important sentinels of the immune system, which can sense and respond to danger, restrict pathogens by intracellular killing pathways and regulate wide-ranging immune responses, they also host a number of important human pathogens such as HIV-1 and Mycobacterium tuberculosis. Hence we are interested in the mechanisms by which these pathogens can either evade host defence mechanisms in macrophages or stimulate harmful immune responses. Our work extends from in vitro laboratory models to challenge experiments in humans and sampling of tissues at the site of disease in order to understand host-pathogen interactions in vivo. In view of the multivariate complexity of the immune response in infectious diseases, we extensively use genome wide transcriptional profiling strategies in order to obtain as systems level view together with detailed molecular resolution. We work closely with Prof. Benny Chain's group who focus on developing computational approaches to interrogate high dimensional data in immunology, and Prof. Greg Tower's group who focus on innate immunity to retroviruses.

Mahdad Noursadeghi: UCL Profile

PhD projects - Mahdad Noursadeghi

Existing projects in the group include:

• HIV 1 & Mycobacterium tuberculosis co-infection in macrophages
• Defining protective immunity to human tuberculosis
• Augmentation and regulation of immune responses to tuberculosis by vitamin D
• Innate immune governance of the fate of inflammatory monocytes in tuberculosis
• Targeting neutrophil recruitment in pneumococcal meningitis.

Relevant publications

1. Tomlinson G, Chimalapati S, Pollard T, Lapp T, Cohen J, Camberlein E, Stafford S, Periselneris J, Aldridge C, Vollmer W, Picard C, Casanova J L, Noursadeghi M, Brown J*. TLR-mediated inflammatory responses to Streptococcus pneumoniae are highly dependent on surface expression of bacterial lipoproteins. J Immunology 2014 (doi:10.4049/jimmunol.1401413).
2. Towers G and Noursadeghi M. Interactions between HIV-1 and the Cell-Autonomous Innate Immune System. 2014. Cell Host & Microbe 2014 (doi: 10.1016/j.chom.2014.06.009).
3. Mlcochova P, Watters S, Towers GJ, Noursadeghi M, Gupta RK. Vpx complementation of 'non-macrophage tropic' R5 viruses reveals robust entry of infectious HIV-1 cores into macrophages. Retrovirology. 2014 (doi: 10.1186/1742-4690-11-25).
4. Kundu R, Chain BM, Coussens AK, Khoo B, Noursadeghi M. Regulation of CYP27B1 and CYP24A1 hydroxylases limits cell autonomous activation of vitamin D in dendritic cells. Eur J Immunol. 2014 (doi: 10.1002/eji.201344157).
5. Tomlinson GS, Bell LCK, Walker NF, Tsang J, Brown JS, Breen R, Lipman M, Katz DR, Miller RF, Chain BM, Elkington PTG, Noursadeghi M. HIV-1 infection of macrophages dysregulates innate immune responses to Mycobacterium tuberculosis by inhibition of interleukin 10. J Infectious Diseases. 2013 (doi: 10.1093/infdis/jit621).
6. Rasaiyaah J, Tan CP, Fletcher AJ, Price AJ, Blondeau C, Hilditch L, Jacques DA, Selwood DL, James LC, Noursadeghi M, Towers GJ*. HIV-1 evades innate immune recognition through specific co-factor recruitment. Nature. 2013. (doi:10.1038/nature12675).
7. Tomlinson GS, Cashmore TJ, Elkington PTG, Yates J, Lehloenya RJ, Tsang J, Brown M, Miller RF, Dheda K, Katz DR, Chain BM, Noursadeghi M. Transcriptional profiling of innate and adaptive human immune responses to mycobacteria in the tuberculin skin test. Eur J Immunol. 2011 (doi:10.1002/eji.201141841).

Dr Laura Pallett

Understanding how resident immune cells adapt to survive and function long-term in the human liver.

In the Pallett lab we study how resident immune cells (i.e. those that no longer recirculate) adapt once they enter the liver environment. We are particularly interested in the cellular ‘conversations’ happening between immune cells (particularly T and B cells) and the underlying stroma and how these conversations impact phenotype, function and metabolic preference.

Our previous work has highlighted the importance of a highly specialised population of memory T cells, named tissue-resident T cells (or TRM) that reside permanently within the liver for over a decade. We know these cells are essential ‘frontline immune sentinels’ able to mediate rapid antiviral and anti-tumour responses. But as we are leaning more about these cells, the more it is emerging that these cells may have a dark side, playing a potentially damaging role within tissues, as they become activated in unconventional ways.

Why do we care? In 2018 cirrhosis (and associated liver disease) was named the leading cause of mortality in individuals aged 35-49 in the UK. Worldwide cirrhosis, and its complications cause >1.32 million deaths each year, with many considered preventable due to the growing contribution of obesity and alcohol misuse. But as it stands, there are no direct anti-fibrotic treatments available, so there is an urgent unmet clinical need to understand immunological mechanisms of fibrosis / cirrhosis to uncover potential new avenues for therapeutic intervention.

Laura Pallett: UCL Profile

PhD projects - Laura Pallett

If you would like to join us in the Pallett lab, you will have the opportunity to work on a dynamic project to unravel bits of the cellular 'conversations' occurring within the human liver.

The project will involve working closely with our clinical colleagues to obtain high-quality tissue samples, and exciting state-of-the-art technologies, such as multiplex imaging, spectral flow cytometry and the generation of novel 3D cell-culture systems (to mimic the fibrotic liver in vitro).

The project will be co-supervised by myself and Prof. Mala Maini so you would become part of a highly productive multi-disciplinary team with a fantastic track record of supervision and fun.

Relevant publications

1. Pallett L.J. et al. Nature (2023) 'Tissue CD14+CD8+ T cells reprogrammed by myeloid cells and modulated by LPS'
2. Pallett L.J. et al. JEM (2017) 'IL-2high tissue-resident T cells in the human liver: Sentinels for hepatotropic infection'
3. Gill U.S. & Pallett L.J. et al. Gut (2019) 'Fine needle aspirates comprehensively sample intrahepatic immunity'
4. Pallett L.J. & Burton A.R. et al. JEM (2020) 'Longevity and replenishment of human liver-resident memory T cells and mononuclear phagocyte'
5. Ichikawa T. et al. Nat Immunol (2019) 'CD103hi Treg cells constrain lung fibrosis induced by CD103lo tissue-resident pathogenic CD4 T cells'

Dr Dimitra Peppa

The Peppa lab has an interest in chronic viral diseases (HBV, HIV) and emerging viral infections (SARS-CoV-2) of global health significance with a strong focus on translational research. Our research work benefits from unprecedented access to one of the largest and well characterised clinical cohorts of people living with HIV and viral hepatitis patients; these groups of patients suffer detrimental health care outcomes associated with immune dysfunction, ongoing inflammation, accelerated ageing and increased vulnerability to emerging infections. Our aim is to increase our understanding of the role of key immune cell components, in particular Natural Killer cells, during viral disease that can be harnessed to improve the lives of our patients.

The Pears Building provides world-class laboratory facilities for virology, immunology, and clinical research. Outstanding research amenities at include equipment and services for cellular immunology (state-of-the-art flow cytometry facilities), immunometabolism (Seahorse technology), molecular and experimental medicine, human genomics, vaccine development, cellular imaging, genetic engineering, and bioinformatics.

Dimitra Peppa: UCL Profile

PhD projects - Dimitra Peppa

Available projects include:

• Identification of novel therapeutic targets and/or predictive biomarkers: This project involves integration of ‘omic technologies’ to infer regulatory networks and drivers of immunity and ongoing inflammation in distinct anatomical compartments in patients with HIV and CMV coinfection. This high-resolution strategy will enable patient monitoring and stratification for therapeutic interventions to prevent comorbidities associated with premature ageing.
• Development of NK based cellular therapeutics: Develop a scalable platform for the expansion of adaptive NK cells with enhanced functionality and predictable selectivity. Genetic engineer human NK cells with features that improve their capacity to recognise and kill HIV- and HBV-infected target cells (in collaboration with Waggoner Lab, USA). This approach could circumvent many of the limitations inherent to the current immunotherapeutic approaches as a novel therapeutic avenue for viral disease.
• HIV related immunosuppression and responses to SARS-CoV-2: There is currently little information on vaccine efficacy/correlates of protection in this vulnerable population group. This work will examine the development of specialised NK cell populations exhibiting memory-like features in response to natural infection and vaccination with implications for the development of new vaccine targets.

 

Relevant publications

1. Touizer E, Alrubayyi A, Rees-Spear C, Fisher-Pearson N, Griffith S, Muir L, Pellegrino P, Waters L, Burns F, Kinloch S, Rowland-Jones S, Gupta K R, Gilosn R, Peppa D, McCoy L. Failure to seroconvert after two doses of BNT162b2 SARS-CoV-2 vaccine in uncontrolled HIV infection. Lancet HIV May 2021.
2. Aljawharah Alrubayyi, Ester Gea-Mallorquí, Emma Touizer, Dan Hameiri-Bowen, Jakub Kopycinski, Bethany Charlton, Natasha Fisher-Pearson, Luke Muir, Annachiara Rosa, Chloe Roustan, Christopher Earl, Peter Cherepanov, Pierre Pellegrino, Laura Waters, Fiona Burns, Sabine Kinloch, Tao Dong, Lucy Dorrell, Sarah Rowland-Jones, Laura E. McCoy, Dimitra Peppa. Characterization of humoral and SARS-CoV-2 specific T cell responses in people living with HIV. Nat Commun 12, 5839 (2021). https://doi.org/10.1038/s41467-021-26137-7
3. Gupta RK, Abdul-Jawad S, McCoy LE, Mok HP, Peppa D, Salgado M, Martinez-Picado J, Nijhuis M, Wensing AMJ, Lee H  et al. HIV-1 remission following CCR5Δ32/Δ32 haematopoietic stem-cell transplantation. Nature 2019 10.1038/s41586-019-1027-4.
4. Maini MK and Peppa D. Shared immunotherapeutic approaches in HIV and HBV: Combine and Conquer. Current Opinion in HIV and AIDS. 2020 
5. Bradley T, Peppa D, Pedroza-Pacheco I, Li D, Cain DW, Henao R, Venkat V, Hora B, Chen Y, Vandergrift NA, Overman RG, Edwards RW, Woods CW, Tomaras GD, Ferrari G, Ginsburg GS, Connors M, Cohen MS, Moody MA, Borrow P, Haynes BF. RAB11FIP5 expression and altered natural killer cell function are associated with induction of HIV broadly neutralizing antibody responses, Cell 2018 Oct 4;175(2): 387-399e17.
6. Peppa D, Pedroza-Pacheco I, Pellegrino P, Williams I, Maini MK, Borrow P. Adaptive Reconfiguration of Natural Killer Cells in HIV-1 Infection. Front Immunol. 2018 Mar 16;9: 474.
7. Peppa D, Gill US, Reynolds G, Easom NJ, Pallett LJ, Schurich A, Micco L, Nebbia G, Singh HD, Adams DH, Kennedy PT, Maini MK. Up-regulation of a death receptor renders antiviral T cells susceptible to NK cell-mediated deletion. J Exp Med. 2013 Jan 14;210(1): 99-114.

Dr Anne Pesenacker

Immune regulation via co-stimulatory, co-inhibitory receptors and regulatory T cells in health and autoimmunity

CD4+ Regulatory T cells (Tregs) are crucial to maintain tolerance, balancing effector T cell responses to harmful agents and suppressing unwanted responses. However, too little control may lead to autoimmunity (e.g. juvenile idiopathic arthritis or type 1 diabetes), while too much control may contribute to the development of cancers. Co-stimulatory and co-inhibitory receptors are crucial to determine functional outcomes upon activation. We are focussing on the relatively novel co-receptor family of CD96, CD226 and TIGIT, receptors highly expressed on Tregs but with little understanding of their function, and who share the ligand CD155. The pathway has been implicated in autoimmunity and cancer. We aim to elucidate the CD226, TIGIT and CD96 signalling, receptor-receptor and receptor-ligand interactions and study their role in primary human Treg function in health and disease.

Moreover, we currently lack Treg-specific markers and functional experiments are complex and may not represent in vivo activity. Therefore, we have established a clinically-applicable Treg gene signature that reflects Treg “fitness” as a possible biomarker assay and to help us understand how Tregs are dysfunctional at the site of inflammation. A full PhD project with the studies being extended and would likely focus on the mechanistic basis behind altered Treg fitness in disease

The Pesenacker lab is using cellular and molecular immunology techniques, including the cutting-edge gene-editing system CRISPR-Cas9, cloning, cell culture, primary Treg expansion and editing, advanced flow cytometry, confocal microscopy and nanoString analysis, including biomarker discovery pipeline. 

Anne Pesenacker: UCL Profile

PhD projects - Anne Pesenacker

CD96, CD226 and TIGIT co-receptor family as immune regulators

• Functional differences between CD96 variants 
• Receptor-receptor-ligand interaction
• Co-receptor intracellular receptor trafficking/signalling upon ligation
• Role of co-receptors in Treg function

Treg gene signature as measure of Treg fitness

• Utilizing the Treg gene and protein signatures as biomarker for disease activity
• Understanding how the Treg signature genes/proteins define Treg fitness functionally
• Can Treg-targeted therapeutic approaches re-set Treg signatures?

Notably, any project will directly contribute to ongoing work in the Pesenacker lab and projects are subject to change and can be personalised. For more information, do not hesitate to get in touch.

Relevant publications

1. Attrill MH, Shinko D … Pesenacker AM. Treg fitness as a biomarker for disease activity in Juvenile Idiopathic Arthritis. bioRxiv. 2024:2024.04.24.590917. (2024). DOI: 10.1101/2024.04.24.590917
2. Attrill MH, Shinko D … Pesenacker AM. The immune landscape of the inflamed joint defined by spectral flow cytometry. BioRxiv. 2023:2023.11.30.569010. (2023). DOI: 10.1101/2023.11.30.569010
3. Pesenacker AM, et al. Treg gene signatures predict and measure type 1 diabetes trajectory. JCI insight. 2019;4(6). DOI: 10.1172/jci.insight.123879
4. Pesenacker AM, et al. A Regulatory T-Cell Gene Signature Is a Specific and Sensitive Biomarker to Identify Children With New-Onset Type 1 Diabetes. Diabetes. 2016;65(4):1031-9. DOI:10.2337/db15-0572
5. Lam, AJ et al. Optimized CRISPR-mediated gene knockin reveals FOXP3-independent maintenance of human Treg identity. Cell reports 36, 109494 (2021).

Dr Matthew Reeves

Molecular basis of human cytomegalovirus pathogenesis

Our research concentrates on the mechanisms human cytomegalovirus (HCMV) employs to promote, sustain and reactivate lifelong latent infections of the host.

As obligate parasites, viruses must usurp, disable or re-prioritise key cellular processes for their own replication and survival and thus we investigate the molecular details of the interaction of HCMV with the host cell. We are also interested how the interaction of HCMV with the cell impacts on immune surveillance.

Thus, we take a mechanistic approach to generate an understanding of HCMV persistence and pathogenesis in vivo and, consequently, the development of strategies to target it therapeutically.

Matt Reeves: UCL Profile

PhD projects - Matthew Reeves

Host and Viral molecular determinants of HCMV latency and reactivation

Latency and reactivation reflects a 'molecular dance' with the cell. Our current research is aimed at understanding key cellular signalling pathways that dictate the latent/reactivation switch and, by extension, the role a subset of viral gene products play in controlling this. Our current major interest is on a virally encoded deSUMOylase activity (LUNA) we characterised as an antagonist of innate immunity. We hypothesise the enzymatic activity of LUNA provides HCMV with the capacity to manipulate multiple host processes providing a fundamental tool to study host cell biology.

The immune response to HCMV and vaccination

HCMV dedicates over 40% of its 230kb genome to immune evasion strategies – enabling it to counter a prodigious host immune response. We are interested in the aspects of that response which are potently anti-viral to learn more about the control of chronic infections in vivo and help guide our ongoing efforts to develop an urgently needed vaccine against HCMV.

HCMV as a tool to understand haematopoiesis

HCMV establishes latency in pluripotent bone marrow progenitors yet is selectively carried in the cells of the myeloid lineage. Thus we are using HCMV as a tool to understand the fundamental mechanisms that promote myeloid cell commitment complementing systems level approaches (scRNAseq, ATACseq) with reductionist studies to describe the phenotype and dissect the mechanisms involved.

More about the lab

Relevant publications

1. Mason et al (2023) J. Gen. Virol. 104(9)
2. Gomes A. et al (2023) J. Gen. Virol. 104(6)
3. Murray M. et al (2023) J. Biol. Chem. 299(6):104727
4. Forrest C. et al (2023) Nature Comms. 14(1):1409
5. Gomes A.  et al (2023) Nature Comms. 14(1):1041
6. Mason R et al (2020) J. Gen. Virol. 101(6):635-44
7. Murray M.J. et al (2020) J. Virol. 94 (7):e02012-19
8. Baraniak, I. et al (2019) Lancet EBioMedicine 50:45-54
9. Dupont L. et al (2019) J. Biol. Chem. 294(35):12901-1291
10. Baraniak I. et al (2019) J. Inf. Dis. 220(2):228-232
11. Poole E.L. et al (2018) Cell Reports 24(3):594-606
12. Baraniak I et al (2018) PNAS 115(24):6273-6278

Professor David Sansom

Understanding the CD28/CTLA-4 pathway in the control of T cell responses

The adaptive immune response (T cells and B cells) provides long lasting specific protection against constantly evolving pathogens. This requires a vast array of receptors (TCR and BCR) to be generated to cover all possible pathogens and is achieved by randomly generating millions of highly diverse receptors. The downside to this process is that receptors can be generated that are capable of recognizing our own tissues resulting in autoimmune diseases. The CD28/ CTLA-4 pathway is involved in preventing this from happening and loss of CTLA-4 in mice and humans results in profound and often fatal autoimmune disease.

The Sansom Lab works on understanding the molecular and cellular mechanisms of CD28/ CTLA-4 function and the impact of their mutation in disease. The CD28/ CTLA-4 pathway consists of a stimulatory receptor (CD28) and an inhibitory receptor (CTLA-4), which bind to two shared ligands with varying affinities. My lab discovered a new biological process (transendocytosis) whereby CTLA-4 effectively captures and destroys the ligands, which stimulate CD28. This mechanism is used by regulatory T cells to suppress T cell activation.

My lab uses a variety of approaches involving molecular biology- cloning and expression of genes, study of clinical mutations, cell biology and in vitro immunology approaches to understand the fundamental properties of this system. The work utilizes extensive cell culture, immune cell function, flow cytometry, confocal microscopy, and mathematical modeling approaches to address these questions.

David Sansom: UCL Profile

PhD projects - David Sansom

Potential PhD project areas include:

1. Studying the impact of patient-derived mutations in CTLA-4, CD80 and CD86 pathways.
2. Investigating the differential functions of CD80 and CD86 in immune responses.
3. Understanding the molecular mechanism of Transendocytosis.

Relevant publications

1. Qureshi, O.S., et al. (2011). Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science 332, 600-603.
2. Schubert, D., et al. (2014). Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nature Medicine 20, 1410-1416.
3. Soskic, B., et.al., (2014). A Transendocytosis Perspective on the CD28/CTLA-4 Pathway. Adv Immunol 124, 95-136.
4. Walker, L.S., and Sansom, D.M. (2015). Confusing signals: Recent progress in CTLA-4 biology. Trends in immunology 36, 63-70.
5. Hou, T.Z. et.al.,(2015). A Transendocytosis model of CTLA-4 function predicts its suppressive behaviour on regulatory T cells. J Immunol 194, 2148-2159.
6. Sansom, D.M. (2015). Moving CTLA-4 from the trash to recycling. Science 349, 377-378.

Professor Benedict Seddon

Defining the cellular and molecular mechanisms controlling T cell immunity

The immune system has evolved specific homeostatic mechanisms to ensure that both the numbers and antigen-recognition receptor diversity of T cells are maintained at relatively constant levels for much of our lifetimes. There are many disease conditions, however, ranging from acquired or genetic immunodeficiencies, to autoimmune diseases and ageing, in which T cell homeostasis is disrupted. This can lead to lymphopenia, shifts in TCR repertoires, reduced responsiveness to vaccines, and increased susceptibility to infection and cancer.

Under normal conditions, T cells exist in multiple sub-compartments with overlapping requirements for survival, and form a huge ‘ecosystem’ of competing or co-existing 'species' defined by their TCR specificity, age and experience of past infections. A systems understanding of the complex dynamics underlying T cell homeostasis will allow us to target interventions for these immune disorders and re-establish normal T lymphocyte immunity.

The aim of my lab is to better understand the cellular and molecular mechanisms controlling maintenance and function of T cells to sustain immunity throughout life. We do this using sophisticated mouse genetics to manipulate signaling pathways and transcription factors such as NF-κB and in vivo challenge models of viral infection (influenza A, CMV) and tumour models to test immune function.

Benedict Seddon: UCL Profile

PhD projects - Benedict Seddon

The PhD project will augment ongoing studies and provide training in molecular, cellular and/or computational immunology. The Seddon laboratory is located in the newly opened Institute of Immunity and Transplantation at the Royal Free Hospital, that offers state of the art facilities and training environment.

The Seddon laboratory has an excellent track record of PhD student training - all students finish with one or more first author papers.

Relevant publications

Example Papers from past PhD students (marked in bold)

1. F. Carty, S. Layzell, A. Barbarulo, F. Islam, L.V. Webb, and B. Seddon. 2023. IKK promotes naive T cell survival by repressing RIPK1-dependent apoptosis and activating NF-kappaB. Sci Signal 16:eabo4094.
2. Verheijen, M., S. Rane, C. Pearson, A.J. Yates, and B. Seddon. 2020. Fate Mapping Quantifies the Dynamics of B Cell Development and Activation throughout Life. Cell Rep 33:108376.
3. Webb, L.V., A. Barbarulo, J. Huysentruyt, T. Vanden Berghe, N. Takahashi, S. Ley, P. Vandenabeele, and B. Seddon. 2019. Survival of Single Positive Thymocytes Depends upon Developmental Control of RIPK1 Kinase Signaling by the IKK Complex Independent of NF-κB. Immunity 50:348-361.e344.
4. Webb, L.V., S.C. Ley, and B. Seddon. 2016. J Exp Med 213:1399-1407.
5. Schim van der Loeff, I., L.Y. Hsu, M. Saini, A. Weiss, and B. Seddon. 2014. J Immunol 193:2873-2880.
6. Marshall, D., C. Sinclair, S. Tung, and B. Seddon. 2014. J Immunol 193:5525-5533.
7. Sinclair, C., Bains, I., Yates, A. and B. Seddon 2013. PNAS. 110 (31), E2905-E2914
8. Sinclair, C., Saini, M., van der Loeff, I.S., Sakaguchi, S., and Seddon, B. 2011. Sci Signal 4, ra77.

Professor Hans Stauss

The main focus of our research is the analysis of antigen-specific T lymphocyte responses to tumours and the development of immunotherapy approaches for the treatment of cancer and chronic infection.

In order to generate therapeutic T cells of desired specificity we use retroviral vectors to transfer the genes encoding antigen-specific T cell receptors (TCR) and chimeric antigen receptors (CAR) into primary T cells. We have developed strategies to improve the expression and function of therapeutic TCR, and we use animal models to test the efficacy of tumour protection in vivo. We perform molecular and cellular studies with gene engineered human T cells and with murine T cells. At present we are recruiting patients into two clinical trials testing the concept of TCR gene therapy in humans.

We also employ genetic engineering to regulate the metabolic activity of gene modified T cells, with the goal to either enhance effector T cell differentiation or memory formation in vivo. The CRISPR technology is used to perform targeted gene editing, which allows us to disrupt genes encoding proteins that are involved in triggering the exhaustion of therapeutic T cells. Finally, we have used the transfer of TCR and CAR into regulatory T cells to achieve antigen-specific immune suppression in vivo as potential treatment for autoimmune conditions.

Hans Stauss: UCL Profile

Dr Leo Swadling

The T cell vaccines lab

Our research aims to establish which are the 'best' T cells at controlling a given viral infection.

We investigate this by integrating single-cell studies of T-cell quality (function, phenotype, trafficking) and specificity (virus, protein, epitope, TCR clonality) at the extremes of controlled or uncontrolled viral infections, and by developing T cell vaccines.

Keywords

• T cells
• viruses
• vaccines
• machine learning
• coronaviruses
• SARS-CoV-2
• HCV
• HBV
• tissue-residency
• T cell receptor repertoire
• scRNAseq.

Leo Swadling: UCL Profile

PhD projects - Leo Swadling

Defining T cell correlates of protection in people who resist SARS-CoV-2 infection

We identified an association between T cells targeting the essential highly conserved replication-transcription proteins of SARS-CoV-2 (e.g., polymerase and helicase) and protection from a detectable infection (Abortive infection; Swadling et al Nature 2022), we are now characterising this population of T cells to identify qualities and specificities that best correlate with protection. With Prof. Maini and Prof. Barnes (Uni of Oxford) we are testing designs for a pan-coronavirus vaccines based on this work.

Rational Design of cross-protective T cell vaccines

We are particularly interested in understanding ‘what determines the ability of a T cell to cross-recognise different viral variants or even different viruses’ and how vaccines can be rationally designed to induce the most cross-protective immunity. We are studying viral sequence evolution (Lucy van Dorp, UCL Genetics) and TCR characteristics (Dr Andreas Mayer, ULC) at cross-reactive epitopes to allow prioritisation of epitopes for inclusion in T cell vaccines.  

Bioinformatic Delineation of the TCR signature of HBV control

We are identifying protective TCR sequences from the site of infection, the liver, for use in next generation TCR gene therapy for hepatitis-B virus and to probe the biological link between specificity and function. We are also investigating T cell adaptation to the liver environment.

Relevant publications

• Swadling et al. Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2 (2022) Nature. DOI: 10.1038/s41586-021-04186-8.
• Cankat et al. In search of a pan-coronavirus vaccine: next-generation vaccine design and immune mechanisms Cell Mol Immunol. 2024 Feb;21(2):103-118.
• Diniz et al. T cell control of SARS-CoV-2:When, Which and Where? (2023) Semin Immunol. doi: 10.1016/j.smim.2023.101828
• Swadling et al. Human Liver Memory CD8+ T Cells Use Autophagy for Tissue Residence. (2020) Cell Rep. DOI: 10.1016/j.celrep.2019.12.050

Dr Yasu Takeuchi

Reader in Molecular Virology, Division of Infection & Immunity.

Yasu Takeuchi: UCL Profile

PhD projects - Yasu Takeuchi

Emerging Virus Preparedness: Use of Gene Therapy Vectors

The current COVID-19 pandemic highlights importance of preparedness against emerging infectious diseases. While it is difficult to predict what pathogens will cause future pandemics, influenza viruses remain major suspects with high potential to cause pandemics. Furthermore, there are several regionally emerging viruses prioritised in the World Health Organisation (WHO) R&D Blueprint [1], including viruses like Zika virus (ZIKV) which in 2016 was declared a Public Health Emergency of International Concern. Many such viruses are currently the cause of tropical diseases with the potential to spread to temperate regions due to climate change.

Here I propose two possible PhD projects with the theme of emerging virus preparedness, both in collaboration with The Medicines and Healthcare products Regulatory Agency, Science, Research and Innovation (MHRA, SRI).

Universal immunoprophylaxis against influenza viruses by gene-delivered nanobodies (in collaboration with Dr Simon Hufton, Biotherapeutics and Advanced Therapies, MHRA)

We have been developing alpaca-derived, cross-subtype neutralizing single domain antibodies (nanobodies) against influenza and their delivery using gene therapy vectors [2]. This gene-mediated immunoprophylaxis approach may allow us to protect the high-risk population with poor vaccine response (e.g. immunocompromised patients, elderly etc) from a wide range of influenza strains including those new to humans with high pandemic potential. Further development includes broadening target strains, ‘humanisation’ of the nanobody constructs and optimization of nanobody effector function.

The student will study biochemistry and structural biology of nanobody-pathogen interaction, immunology focusing on nanobodyhost immune system interaction and gene therapy technology.

Development of pseudotypes of viruses with global epidemic potential (in collaboration with Dr Giada Mattiuzzo, Vaccines, MHRA)

The Emerging Virus Group at NIBSC has been contributing to a rapid response to emergencies caused by enveloped viruses by developing standards and assays for diagnostics and serology. These activities heavily rely on pseudotype virus (PV) technology based on gene therapy vector systems [3] which enables us to study dangerous viruses more safely and outside special containment like BSL3/4. While it has been relatively easy to make PVs for viruses that bud at the cell surface, e.g. Ebola virus, MERS [4] and SARS CoV-2 coronaviruses, we recognise our shortcomings in making PVs for viruses that bud intracellularly, e.g. flaviviruses (dengue, zika etc).

This project will explore and compare current and new PV systems in order to increase our capability in PV making and assay development for a wider range of viruses including those yet unknown.

Relevant publications

1. https://www.who.int/activities/prioritizing-diseases-for-research-and-de...
2. https://www.frontiersin.org/articles/10.3389/fimmu.2020.00627/full
3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6118154/?report=classic
4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759245/

Dr Andreas Tiffeau-Mayer

T cell repertoire as a complex ecosystem

The evolution of diverse clonal populations underlies the development of cancers, antibiotic resistance, and protective immune responses. Predicting outcomes of the dynamical processes shaping clonal evolution is of considerable practical importance, but the current theory breaks down when analysing highly diverse populations where there are many distinct clones.

An important example of such a system is the adaptive immune system, where the highly diverse antigen receptors act as natural genetic 'barcodes' for identifying clonal lineages, which can be read out by sequencing at scale.

Andreas Tiffeau-Mayer: UCL Profile

PhD projects - Andreas Tiffeau-Mayer

In this PhD project, we will develop computational and mathematical techniques to understand the dynamic processes, which regulate the extremely diverse population of T cells, and their response to antigen.

As a PhD student, you have access to unique longitudinal sequencing data on T cell receptor repertoires in the context of BCG vaccination, tuberculosis infection and treatment of COVID-19 infection.

The project will address key questions such as the longevity of the immune response, and how this relates to the the dynamics of individual T cell clones. For example, we have recently shown that early exposures in infancy leave an outsized, life-long imprint on the T cell clonal hierarchy (Gaimann et al. eLife 2020).

On the theory side, you will become an expert in mathematical models of stochastic processes and in Bayesian statistics, both key skills that will only grow in importance across the multitude of fields becoming increasingly data-rich.

Relevant publications

1. Mayer A, Callan CG Jr. Measures of epitope binding degeneracy from T cell receptor repertoires. Proc Natl Acad Sci U S A. 2023 Jan 24;120(4):e2213264120. doi: 10.1073/pnas.2213264120.
2. Milighetti M, Peng Y, Tan C, Mark M, Nageswaran G, Byrne S, Ronel T, Peacock T, Mayer A, et al. Large clones of pre-existing T cells drive early immunity against SARS-COV-2 and LCMV infection. iScience. 2023 Jun 16;26(6):106937. doi: 10.1016/j.isci.2023.106937.
3. Gaimann MU, Nguyen M, Desponds J, Mayer A. Early life imprints the hierarchy of T cell clone sizes. Elife. 2020 Dec 21;9:e61639. doi: 10.7554/eLife.61639.

Professor Pavel Tolar

B cell signalling and antigen presentation in immune protection and pathology

B cells are critical for antibody-mediated protection from infections, but sometimes overreact and cause immune pathology. We are interested in the fundamental mechanisms by which B cells detect and respond to invading pathogens that can explain the balance of the positive and negative outcomes.

We have pioneered the idea that the B cell antigen receptor (BCR) uses mechano-sensitivity to discriminate the binding to antigens. We are now dissecting the molecular pathways by which the BCR regulates B cell activation and antigen presentation under a variety of conditions to understand how these pathways promote protective antibody responses, particularly after immunization. Conversely, we are investigating how BCR signalling sometimes causes abnormal B cell activation and immune pathology, such as autoimmunity, allergy and B cell lymphoma.

We use a variety of approaches including molecular immunology, mouse genetics, CRISPR gene editing, biophysics, bioinformatics and live-cell imaging to answer these questions. Our diverse expertise in these areas creates an environment that promotes the development of independent and creative researchers, including some very successful PhD students.

Pavel Tolar: UCL Profile

PhD projects - Pavel Tolar

Examples of possible projects in the lab include:

1. Regulation of B cell germinal centre reactions by antigen retention on follicular dendritic cells
2. Identification of novel mechanisms controlling IgE B cell responses in allergy
3. Mapping of pathways promoting the pathogenesis and transformation of B cell lymphomas

Relevant publications

1. Martínez-Riaño, A., Wang, S., Boeing, S., Minoughan, S., Casal, A., Spillane, K. M., Ludewig, B. & Tolar, P. (2023) Long-term retention of antigens in germinal centers is controlled by the spatial organization of the follicular dendritic cell network. Nat. Immunol. 24, 1281-1294.
2. Chen, Q., Menon, R. P., Masino, L., Tolar, P.* & Rosenthal, P. B. (2023) Structural basis for Fc receptor recognition of immunoglobulin M. Nat. Struct. Mol. Biol. 30, 1033-1039. 
3. Newman, R. and Tolar, P. (2021) Chronic calcium signaling in IgE+ B cells limits plasma cell differentiation and survival. Immunity 54, 2756-2771.e10.
4. Spillane, K. M., Tolar, P. (2017) B cell antigen extraction is regulated by the physical properties of antigen presenting cells. J. Cell Biol. 216, 217-230.
5. Nowosad, C. R., Spillane, K. M., and Tolar, P. (2016) Germinal center B cells recognize antigen through a specialized immune synapse architecture. Nat Immunol 17, 870-77.
6. Natkanski, E., Lee, W.-Y., Mistry, B., Casal, A., Molloy, J.E., and Tolar, P. (2013) B cells use mechanical energy to discriminate antigen affinities. Science 340, 1587-1590.

Professor Greg Towers

Host-Virus Interactions, evasion of innate immune sensing and pandemic potential

Why do some viruses infect a few people and disappear, whereas others infect everyone. Why do some viruses kill you and if they can kill one person, why don’t they kill everyone? What are the special features of a pandemic virus and how can we spot these features in viruses that are still restricted to the jungle? We think that the answers to these questions lie in understanding the details of host virus interactions and how viruses manipulate the host response to facilitate infection and transmission. All viruses elicit a host response on infection and all viruses are impacted by the host response that they provoke. We take a comparative virology approach to characterising host responses to infection.

We have discovered that pandemic HIV is different to its non-pandemic counterparts through its evasion of innate immune effectors TRIM5, cGAS and TREX1 (ref. 1). We find that SARS-CoV-2 variants of concern are evolving to increase their capacity to evade and antagonise innate immune sensing (2-4). We find that understanding host responses to infection can even help us make gene therapy work more efficiently by inhibiting antiviral host responses (5). We also think that innate immune activation plays an important role in cancer treatment and outcome.

We take a multidisciplinary approach to discovery using molecular virology and accessing structural biology, computational evolution studies and high throughput microscopy through collaboration. We study the mechanisms by which viruses escape innate immune defences and consider how this explains pandemic potential and pathogenicity. We currently study HIV, SARS-CoV-2, MERS, Zika Virus, Dengue Virus and Hepatitis C Virus. We are excited by recent breakthroughs in studying epigenetic regulation of host gene expression, protein phase separation and how it influences viral protein function, and the use of AI to predict protein structures and interpret complex datasets.

Greg Towers: UCL Profile

PhD projects - Greg Towers

Our PhD students develop their projects depending on their interests, skill sets and what's most exciting on the day they arrive.

Relevant publications

1. Zuliani Alvarez et al Evasion of cGAS and TRIM5 defines pandemic HIV. Nat Microbiol. 2022 Nov;7(11): 1762-1776
2. Thorne et al Evolution of enhanced innate immune evasion by SARS-CoV-2. Nature 2022 Feb;602(7897): 487-495
3. Bouhaddou et al. SARS-CoV-2 variants evolve convergent strategies to remodel the host response. Cell 2023 Oct 12;186(21): 4597-4614
4. Reuschl et al Evolution of enhanced innate immune suppression by SARS-CoV-2 Omicron subvariants. Nat Microbiol. 2024 Feb;9(2): 451-463
5. Petrillo et al Cyclosporine H Overcomes Innate Immune Restrictions to Improve Lentiviral Transduction and Gene Editing In Human Hematopoietic Stem Cells. Cell Stem Cell 2018 Dec 6;23(6): 820-832.

Professor Lucy Walker

Immune Regulation and Type 1 Diabetes

The Walker lab is interested in understanding how the immune system is regulated such that responses to infectious agents can be mounted yet tolerance to self-tissues is maintained.  Failure of such regulation can lead to the development of autoimmune diseases like Type 1 Diabetes, Rheumatoid Arthritis and Multiple Sclerosis.

The broad areas of interest in the lab are:

• Pathogenesis and regulation of autoimmune diabetes in animal models and Type 1 Diabetes patients
• Regulatory T cell homeostasis and function in vivo
• The role of costimulatory molecules (CD28, CTLA-4) in immune activation and immune regulation
• The development and function of follicular helper T cells.

The group typically comprises around 6-7 researchers. There are currently 2 postdocs, 4 PhD students and 1 research assistant. We hold fortnightly lab meetings and there are also opportunities to present data in larger forums through regular joint lab meetings with other groups within the Institute of Immunity & Transplantation. The lab is funded by an MRC Programme Grant and additional project grant support from Diabetes UK, the European Union, the Rosetrees Trust and MedImmune.

Lucy Walker: UCL Profile

Dr Alan Xiaodong Zhuang

Unlock the Body’s Biological Clock to Fight Viral Infections
 
Are you ready to explore the cutting edge of immunology and circadian biology? Our lab focuses on how the body’s 24-hour internal clock - the circadian rhythm - shapes our immune responses, with a focus on Hepatitis B Virus (HBV), a major global health threat linked to liver cancer. Understanding how circadian pathways regulate immune responses could revolutionise treatments for HBV and other infections.

Why HBV? HBV infects over 270 million people globally, claiming 880,000 lives annually. Current treatments reduce viral loads but are not curative, leaving patients vulnerable to liver diseases, including cancer. Our team has made exciting discoveries - we've identified a key role for the circadian clock in controlling HBV replication and influencing T-cell function. We are exploring using this knowledge to enhance immunity or improve the efficacy of HBV vaccines based on the time of day.

Alan Xiaodong Zhuang: UCL Profile

PhD projects - Dr Alan Zhuang

This PhD offers an incredible opportunity to work on groundbreaking research, directly impacting our understanding of how circadian rhythms affect immune responses to viral infections. You'll gain hands-on experience with cutting-edge tools, including multi-color flow cytometry, immune assays, in vitro and in vivo circadian and infection models, and the latest RNA-scope and spatial transcriptomics technology. Working closely with clinical samples, you'll help uncover new therapeutic strategies for one of the world's deadliest viruses.

Key questions we aim to answer

1. How does the circadian clock regulate T-cell responses to HBV? – Discover the critical interactions between our internal biological clock and the immune system’s ability to fight viral infections.
2. Can manipulating circadian rhythms enhance the effectiveness of HBV vaccines? – Explore how the time-of-day impacts vaccine efficacy and uncover potential breakthroughs in immunisation strategies.
3. What role do circadian disruptions play in chronic HBV infection and liver disease progression? – Unveil the consequences of disrupted clock pathways in patients and identify new ways to restore immune function.

Join us and work alongside our world-class collaborators, including Prof. Mala Maini, Dr Laura Pallett, and Dr Leo Swadling, as part of a multidisciplinary team with an outstanding track record.

This is more than just a PhD - it's a unique opportunity to make your mark on global health research.

Relevant publications

1. Borrmann H, Ulkar G, Kliszczak AE, Ismed D ... Zhuang X, McKeating JA. Molecular components of the circadian clock regulate HIV-1 replication. iScience. 2023 May 29;26(7):107007. doi: 10.1016/j.isci.2023.107007.
2. Zhuang X, Edgar RS, McKeating JA. The role of circadian clock pathways in viral replication. Semin Immunopathol. 2022 Mar;44(2):175-182. doi: 10.1007/s00281-021-00908-2. Epub 2022 Feb 22.
3. Zhuang X, Tsukuda S, Wrensch F, Wing PAC, et al. The circadian clock component BMAL1 regulates SARS-CoV-2 entry and replication in lung epithelial cells. iScience. 2021 Oct 22;24(10):103144. doi: 10.1016/j.isci.2021.103144.
4. Zhuang X, Forde D, Tsukuda S, D'Arienzo V, et al. Circadian control of hepatitis B virus replication. Nat Commun. 2021 Mar 12;12(1):1658. doi: 10.1038/s41467-021-21821-0.
5. Wing PA, Davenne T, Wettengel J, Lai AG, Zhuang X, et al. A dual role for SAMHD1 in regulating HBV cccDNA and RT-dependent particle genesis. Life Sci Alliance. 2019 Mar 27;2(2):e201900355. doi: 10.26508/lsa.201900355.

Download project list (Word)