Immunobiology
Research in Immunobiology seeks to elucidate the development, function and regulation of immune cells by applying diverse experimental approaches including molecular and cell biology, transgenic and molecular genetics, including the use of fruit-flies, and state-of-the-art analysis of human samples. Key interests include pathways of lymphocyte and myeloid cell development; mechanisms of autoimmunity; tumour surveillance; the response to virus infection; vaccine and adjuvant development, particularly with respect to HIV; gut B cell biology; and the relationship of immunological and inflammatory processes to metabolism and to ageing. The research teams collectively publish their results in journals of the highest standing such as Science, Nature Immunology, Immunity, Journal of Clinical Investigation, and Journal of Experimental Medicine.
Professor Adrian Hayday: a major focus is on intraepithelial lymphocytes (IEL) – a very large yet poorly understood T lymphocyte compartment residing constitutively within tissues. Compared to their well-studied systemic counterparts, IEL undertake rapid surveillance of molecules denoting tissue dysregulaion, associated with infection, inflammation, and malignancy. The laboratory investigates the molecules and mechanisms underlying such “lymphoid stress-surveillance”, with the potential of IEL to form a novel target for clinical intervention.
Professor Frederic Geissmann: the laboratory aims to define the major pathways of monocyte, macrophage, and dendritic cell (DC) development, and to understand how these cells affect basis physiologic processes, such as metabolism, as well as their roles in innate and adaptive immunity.
Professor Mark Peakman: the structural basis for T cell recognition of human pancreatic antigens in Type 1 diabetes; the mechanisms by which genetic susceptibilities to Type 1 diabetes operate in relation to MHC genes and genes affecting immune regulation; the development of peptide immunotherapy.
Professor Jo Spencer: the function of intestinal IgA is to maintain homeostasis in the lumen of the gut, which is rich in microorganisms and toxins. IgA coats the diverse luminal contents thus agglutinating and stabilising them. Thus, IgA must be both abundant and diverse in its binding repertoire. Our research focuses on how IgA responses are generated and diversified, and how specific responses to intestinal immunisation might be achieved. We examine how the impact of diet and the microbiota on intestinal B cell biology may regulate systemic autoimmunity.
Dr Marie Bijlmakers: antigen recognition by T cells initiates multiple signaling pathways leading to cell proliferation and differentiation. Ubiquitination is an important regulatory mechanism in many cellular processes. The laboratory studies the ubiquitination of key molecules in T cells, such as the tyrosine kinase Lck, and the role of a novel family of ubiquitin ligases genetically implicated in the common inflammatory disease, psoriasis.
Dr Helen Collins: TB remains a major global scourge. Starting from the dependence of mycobacterial infection on metal ions, our laboratory studies mechanisms by which metal ions profoundly influence T cell biology. The development of novel ion chelators may provide a new class of immunosuppressants.
Dr Sandra Diebold: the development of novel cancer vaccines by forming conjugates of antigens, DC-targeting molecules and synthetic mimics of viral nucleic acids. Basic studies into how DC function is affected by cell and tissue damage associated with inflammatory and infectious scenarios.
Dr Marc Dionne: the laboratory employs Drosophila genetics to identify key pathways regulating inflammatory cell behaviour, with focus on how the balance is achieved between positive contributions to host protection against mycobacteria and the negative contributions to tissue damage and inflammatory disease.
Dr Deborah Dunn-Walters: next generation sequencing is employed to define the immunoglobulin repertoire associated with ageing, with different tissues, with vaccination, and with different pathologies. How are key specificities generated and regulated? This can guide strategies to improve vaccination success in vulnerable populations.
Dr Pierre Guermonprez: the impact of infection on the development and functional responsiveness of DC and monocytes; the regulation of monocyte, macrophage, and DC function by lipid bodies and the relationship to artherosclerotic disease where failure of this system may alter key scavenging activities.
Dr Susan John: the IL-2/IL-2 receptor complex is the primary growth factor axis for T cells. Despite intensive study, there is only partial understanding of how its major signaling mediators, Stat5a and Stat5b, profoundly affect T cell biology. The lab identifies and characterizes targets of Stat5 activation in health and disease, and has thereby identified a novel mechanism of T cell regulation.
Dr Linda Klavinskis: HIV1 is currently responsible for more deaths than any other infectious agent, and yet we have neither an effective vaccine nor prophylactic antiviral agents accessible to most of those at risk. Our research aims to increase understanding of how different innate signals, mediated by distinct DC functions, dictate the magnitude of the CD8 T cell memory pool, which is critical in developing effective vaccines. We aim thereby to design better vaccine immunogens and delivery vectors to elicit systemic and mucosal neutralising antibody and T cell responses.
Dr Leonie Taams: using human cells and clinical materials, coupled with high-resolution imaging, the laboratory investigates molecules and pathways by which monocytes regulate the balance of regulatory T cells, and potentially pathogenic, interleukin-17-producing cells, with particular focus on Rheumatoid Arthritis.
Dr Tim Tree: building on recent advancements in understanding peripheral T cell regulation, the laboratory’s research identifies immunoregulatory mechanisms that fail in Type I diabetes. Through collaboration with a large genetics resource in Cambridge, a new level of correlation can be established between immunophenotyping and genotyping, thereby elucidating pathways of pathogenesis. Parallel clinical studies investigate whether immunoregulatory mechanisms can be restored in diabetes-prone or islet transplanted individuals through immunotherapeutic interventions.
Those studies collectively have illuminated several areas, including:
- 'beta-selection', a point in development where gamma delta T cell differentiation diverges from the development of most alpha beta T cells.
- the demonstration that, by contrast to the systemic distribution of diverse alpha beta T cells, gamma delta T cells are disproportionately associated with epithelial tissues, wherein they reside as oligoclonal repertoires of limited diversity.
- the demonstration that gamma delta cells can promote immunoglobulin synthesis by B cells, but that this is primarily self-reactive. In 1998, I assumed the Professorship in Immunobiology at the King's College School of Medicine on the Guy's Hospital site. Our work has continued to provide insight, including:
- identification of the role played by the c-myc proto-oncogene in T cell development
- the demonstration that skin-associated gamma delta T cells protect the skin from potentially pathologic infiltrates of systemic lymphocytes
- the demonstration that gamma delta T cells are a component of the natural resistance to skin carcinogenesis.
- the demonstration that the gene expression pattern that best distinguishes gamma delta T cells from most alpha beta T cells is shared with an unusual set of tissue-associated alpha beta T cells that we collectively term unconventional T cells
- the identification of 'trans-conditioning', a mechanism by which unconventtional T cell differentiation is strongly influenced by alpha beta T cell progenitors.
- the demonstration that trans-conditioning may also affect the body's balance of effector and regulatory T cells Our current research interests focus on how repertoires of tissue-associated unconventional T cells develop and function, including the identification of novel host-encoded molecules expressed by epithelial cells with which gamma delta T cells interact. Research findings are being applied in the clinic, where we have just completed a proof-of-principle trial of gamma delta T cell therapy in hormone-refractory prostate cancer, in collaboration with F Dieli (Palermo).
Research into ageing: Loss of immune system function with age results in the phenomenon termed “Immunosenescence.” This is associated with increased infectious disease morbidity and mortality, poor responses to vaccination, declines in established protective immunity, and increased incidence of autoimmune disorders. Until recently, most age-associated immune failures had been attributed to changes in T cell populations. However, there are many other changes in the immune system and, as data accumulate to show that B cells have a critical role in antigen presentation and regulation - in addition to their role as antibody producers - B cells and humoral immunity becomes highly significant.
High throughput analyses of B cell repertoire are used to investigate dynamics of vaccine responses and age-related changes thereof, primary and secondary immune deficiencies, aetiology of leukaemia/lymphoma, autoimmune diseases.
We aim to advance knowledge of the molecular and cellular mechanisms of inflammation, and to open roads to innovative treatment of inflammation and inflammatory diseases.
We use both molecular approaches and in vivo model system, to investigates the molecular and cellular pathways and networks that control inflammation. Research teams work on basic model of inflammation, as well as on human diseases. Research teams develop extensive collaboration between them and with other groups in the DIIID and in the Randall division and with collaborators accross the world
Tools available in the lab include intravital microscopy, flow cytometry and cell sorting, mouse husbandry, and a Fly lab. A strong core facility for genetics analysis is present on Campus.
The Centre is located in New Hunts House, Guy’s Hospital Campus, and housed together with the Randall division of Molecular Biophysics with his expertise in Molecular and Cell Biology, Physics, Chemistry and Maths, and the MRC Centre for Developmental Neurobiology. Research in the CMCBI is interdiciplinary.
Defining the molecular interactions and signalling events at the monocyte and endothelial cell interface in vivo
A longterm interest is the regulation of the tyrosine kinase Lck, a Src family member that is essential for T cell development and activation. In particular, we have investigated the palmitoylation and ubiquitination of this protein, two dynamic reversible modifications. More recently, we have begun to characterize novel ubiquitin ligases with functions in the immune system. Ubiquitination critically regulates many cellular processes by influencing substrate functions in a variety of degradation-dependent and independent ways, but the proteins that mediate this modification remain poorly characterized. We are specifically studying the functions of the ubiquitin ligase RNF125, which influences T cell activation and may additionally be involved in innate anti-viral responses. A protein related to RNF125, RNF114, was recently identified as a psoriasis susceptibility gene in a whole genome association scan. The functions of this protein, and how it contributes to psoriasis, is another major research area in the lab.
We have an interest in developing new vaccination approaches for tumour immunotherapy. Tumours can express tumour-associated antigens that are recognized by the adaptive immune system. Nevertheless, tumour cells are poor inducers of immune responses since they lack stimuli such as pathogen-associated molecular patterns that efficiently activate the innate immune system. Viral nucleic acids represent ideal, molecularly defined adjuvants to promote the induction of effective anti-tumour immune responses. Therefore, we explore the application of synthetic mimics of viral nucleic acids as adjuvants in the context of tumour immunotherapy.
The biological importance of the JAK-STAT signalling pathway was indicated by the severe combined immunodeficiency (SCID) of patients lacking functional JAK3 kinase, that associates exclusively with the common gamma-chain (γc), which is shared by members of the immunologically important IL-2-family of cytokines. Additionally, genetic mutations in Tyk2, STAT1, STAT3, and STAT5B have been shown to cause various immunodeficiencies, indicating the profound importance of an intact JAK-STAT signaling pathway to normal cellular integrity and immune function.
By virtue of the fact that STAT proteins play vital roles in the proliferative, differentiation and survival decisions of cells, constitutively activated STATs, particularly STAT3 and STAT5, have been detected in a variety of human primary tumours, haematopoietic tumours such as leukaemias, lymphomas, multiple myelomas and cellular transformation by viral or cellular oncogenes. Previously, we showed that dysregulation of STAT5 proteins contributes to the pathology of malignant T cells in Sezary Syndrome. Moreover, over-expression of constitutively activated STAT3 and STAT5, or wild-type or a C-terminally truncated form of Stat5 (Stat5t), induced tumours in transgenic mouse models, suggesting that these two STAT proteins regulate transcription of important target genes, whose aberrant expression can lead to cellular transformation.
We are interested in understanding the molecular mechanisms by which STAT5A, STAT5B and to a lesser extent STAT3, mediate the actions of IL-2 in T cells. As IL-2 regulates many critical aspects of immunity, such as activation induced cell death (AICD) of T cells, tolerance and autoimmunity, via the JAK-STAT5 pathway, a detailed molecular understanding of how these STAT proteins are regulated, and the target genes they regulate should enable us to identify novel therapeutic targets for use in diseases associated with the dysregulation of IL-2/IL-2R system. To this extent we are undertaking structure-function studies of the two highly homologous proteins, STAT5A and STAT5B to understand how they interact with DNA, and whether they differ in this process. In other studies, we have identified a number of novel IL-2-induced target genes of STAT5A and STAT5B by chromatin immunoprecipitation, and studies are underway to validate and evaluate several of these candidate genes at the expression and functional level. We also have on-going collaboration with the lab of Prof. Giovanna Lombardi and Prof. Robert Lechler on the role of STAT3/STAT5 in Treg cell differentiation under inflammatory conditions.
