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Professor Adrian Hayday: we focus on intraepithelial lymphocytes (IEL) which include T lymphocytes constitutively resident within tissues. Compared to their systemic counterparts, IEL are conspicuously under-studied, but they compose a very large T cell subset, and there are already clear indications that they are fundamentally distinct. For example, many are not MHC-restricted; they have a very low threshold for activation; and seem less diverse than naive lymphoid cells. Such properties seem ideal for the rapid surveillance of tissues for the presence of common microbial antigens and/or host 'stress antigens' that denote tissue dysregulaion. Supporting this, we have shown that congenital defects IELs in predispose tissues to inflammatory and malignant pathologies.
Currently, we are focused on understanding the molecules and mechanisms that mediate the recognition of epithelial cells by IEL, and those that determine the development of appropriate IEL repertoires. We utilise molecular and cell biology coupled with novel animal models of immunosurveillance. Additionally, one part of our group focuses on the extrapolation of our findings to human immunosurveillance mechanisms, and their application in the clinic. IEL may compose a sound target for intervention in inflammatory disease and in tumour immunotherapy.
Dr Marie Bijlmakers: antigen recognition by T cells leads to the initiation of multiple signalling pathways, resulting eventually in cell proliferation and differentiation. Ubiquitination has recently been recognised as an important regulatory mechanism involved in many cellular processes. We are studying ubiquitination of key molecules in T cells, such as the tyrosine kinase Lck, and the role of a novel family of ubiquitin ligases in T cell functions.
Dr Sandra Diebold: our laboratory is exploring the use of synthetic mimics of viral nucleic acids as adjuvants for cancer immunotherapy. Viral nucleic acids are potent innate stimuli triggering Toll-like receptor-mediated immune activation with the capacity to induce cellular immunity. We are studying the immunogenicity of these adjuvants in the context of dendritic cell and cancer vaccines for the development of more efficient immunotherapeutic protocols in mouse model systems and in vitro in cultures of primary human cells.
Dr Debra Dunn-Walters lab has particular expertise in the study of immunoglobulin genes. This expertise is used to investigate the dissemination and activation history of B cells in health (eg in vaccination) and disease (eg in malignancies or in autoimmune diseases). We are very interested in the actual processes involved in affinity maturation and the structure/function relationships of immunoglobulin genes. Our research is particularly applied to help understand immunosenescence - the ageing of the immune system resulting in immunological frailty in old age.
Dr Susan John's research interests: IL-2 is a pleiotropic cytokine, which significantly regulates many aspects of immune function, particularly T-cell dependent immune responses, and plays a critical role in mediating immune tolerance. Transmission of signals by the IL-2/IL-2 receptor complex is primarily achieved through the activity of the JAK-STAT signalling pathway; the key components being the tyrosine kinases, JAK1 and JAK3 and the signalling/transcription factors Stat5a, Stat5b and Stat3. We are interested in understanding the molecular mechanisms by which the JAK-STAT pathway facilitates the biological actions of IL-2 in health and disease.
Dr Linda Klavinskis: the Human Immunodeficiency Virus (HIV) is currently responsible for more deaths than any other infectious agent, and yet we have neither an effective vaccine nor prophylactic antiviral agents that are accessible to the majority of those at risk. Our current research themes share the common goals of: i) increasing our understanding how different innate signals dictate the magnitude of the CD8 T cell memory pool which is critical in developing effective vaccines, ii) designing vaccine immunogens and delivery vectors that elicit both systemic and mucosal neutralising antibody and T cell responses to HIV; and iii) increasing our basic understanding of dendritic cell subsets in the skin and how these contribute to inducing efficient T cell responses.
Multi-disciplinary approaches are necessary to address the questions that we are asking: to help us achieve our goals, we have collaborations and partnerships with several local and internationl research groups, and with industry. We hope that via this collaborative approach we can take discoveries in basic science through to their development and application.
Research Details
Dr Jo Spencer's research interest is IgA; intestinal antibody. 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. In order to fulfil this role, IgA is required to both abundant and diverse in its binding repertoire. Our current research focuses on how the IgA response is generated, how it is diversified, and how specific responses to intestinal immunisation can be achieved.
Dr Leonie Taam's research interests include: The research group of Dr Leonie Taams investigates the regulation of the immune response during health and disease. The main research themes in the lab are (i) the effect of CD4+ effector vs. regulatory T cells on monocyte/macrophage function; (ii) the induction and control of human Th17 cells; and (iii) immune regulation of rheumatoid arthritis.
Dr Timothy Tree:
Type 1 diabetes mellitus: an autoimmune disease - the role of islet-specific regulatory T cells in health and disease.
In recent years there has been a considerable expansion in our understanding of the physiology of peripheral T cell immune regulation. This has led to the delineation of several different types of Treg; major examples include T cells co-expressing CD4 and CD25 and T cells producing large amounts of IL-10 and TGFBETA.
Our laboratory focuses on the characterisation of these and recently identified novel populations of Tregs in the context of islet autoimmunity to answer the following questions:
Immunobiology
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DESCRIPTION
Research in Immunobiology applies diverse experimental approaches including molecular and cell biology, transgenic and molecular genetics, and analysis of human samples to elucidate the regulation and function of lymphocytes. Interests include molecules that drive autoimmunity; tumour surveillance; the response to virus infection; vaccine and adjuvant development with respect to HIV and the dysregulation of lymphocytes during lymphomagenesis.Professor Adrian Hayday: we focus on intraepithelial lymphocytes (IEL) which include T lymphocytes constitutively resident within tissues. Compared to their systemic counterparts, IEL are conspicuously under-studied, but they compose a very large T cell subset, and there are already clear indications that they are fundamentally distinct. For example, many are not MHC-restricted; they have a very low threshold for activation; and seem less diverse than naive lymphoid cells. Such properties seem ideal for the rapid surveillance of tissues for the presence of common microbial antigens and/or host 'stress antigens' that denote tissue dysregulaion. Supporting this, we have shown that congenital defects IELs in predispose tissues to inflammatory and malignant pathologies.
Currently, we are focused on understanding the molecules and mechanisms that mediate the recognition of epithelial cells by IEL, and those that determine the development of appropriate IEL repertoires. We utilise molecular and cell biology coupled with novel animal models of immunosurveillance. Additionally, one part of our group focuses on the extrapolation of our findings to human immunosurveillance mechanisms, and their application in the clinic. IEL may compose a sound target for intervention in inflammatory disease and in tumour immunotherapy.
Dr Marie Bijlmakers: antigen recognition by T cells leads to the initiation of multiple signalling pathways, resulting eventually in cell proliferation and differentiation. Ubiquitination has recently been recognised as an important regulatory mechanism involved in many cellular processes. We are studying ubiquitination of key molecules in T cells, such as the tyrosine kinase Lck, and the role of a novel family of ubiquitin ligases in T cell functions.
Dr Sandra Diebold: our laboratory is exploring the use of synthetic mimics of viral nucleic acids as adjuvants for cancer immunotherapy. Viral nucleic acids are potent innate stimuli triggering Toll-like receptor-mediated immune activation with the capacity to induce cellular immunity. We are studying the immunogenicity of these adjuvants in the context of dendritic cell and cancer vaccines for the development of more efficient immunotherapeutic protocols in mouse model systems and in vitro in cultures of primary human cells.
Dr Debra Dunn-Walters lab has particular expertise in the study of immunoglobulin genes. This expertise is used to investigate the dissemination and activation history of B cells in health (eg in vaccination) and disease (eg in malignancies or in autoimmune diseases). We are very interested in the actual processes involved in affinity maturation and the structure/function relationships of immunoglobulin genes. Our research is particularly applied to help understand immunosenescence - the ageing of the immune system resulting in immunological frailty in old age.
Dr Susan John's research interests: IL-2 is a pleiotropic cytokine, which significantly regulates many aspects of immune function, particularly T-cell dependent immune responses, and plays a critical role in mediating immune tolerance. Transmission of signals by the IL-2/IL-2 receptor complex is primarily achieved through the activity of the JAK-STAT signalling pathway; the key components being the tyrosine kinases, JAK1 and JAK3 and the signalling/transcription factors Stat5a, Stat5b and Stat3. We are interested in understanding the molecular mechanisms by which the JAK-STAT pathway facilitates the biological actions of IL-2 in health and disease.
Dr Linda Klavinskis: the Human Immunodeficiency Virus (HIV) is currently responsible for more deaths than any other infectious agent, and yet we have neither an effective vaccine nor prophylactic antiviral agents that are accessible to the majority of those at risk. Our current research themes share the common goals of: i) increasing our understanding how different innate signals dictate the magnitude of the CD8 T cell memory pool which is critical in developing effective vaccines, ii) designing vaccine immunogens and delivery vectors that elicit both systemic and mucosal neutralising antibody and T cell responses to HIV; and iii) increasing our basic understanding of dendritic cell subsets in the skin and how these contribute to inducing efficient T cell responses.
Multi-disciplinary approaches are necessary to address the questions that we are asking: to help us achieve our goals, we have collaborations and partnerships with several local and internationl research groups, and with industry. We hope that via this collaborative approach we can take discoveries in basic science through to their development and application.
Research Details
- Manipulation of innate signals to enhance CD8 T cell memory.
- HIV T cell and neutralising antibody vaccine design and development.
- The biology of Dendritic cell subsets in skin.
Dr Jo Spencer's research interest is IgA; intestinal antibody. 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. In order to fulfil this role, IgA is required to both abundant and diverse in its binding repertoire. Our current research focuses on how the IgA response is generated, how it is diversified, and how specific responses to intestinal immunisation can be achieved.
Dr Leonie Taam's research interests include: The research group of Dr Leonie Taams investigates the regulation of the immune response during health and disease. The main research themes in the lab are (i) the effect of CD4+ effector vs. regulatory T cells on monocyte/macrophage function; (ii) the induction and control of human Th17 cells; and (iii) immune regulation of rheumatoid arthritis.
Dr Timothy Tree:
Type 1 diabetes mellitus: an autoimmune disease - the role of islet-specific regulatory T cells in health and disease.
In recent years there has been a considerable expansion in our understanding of the physiology of peripheral T cell immune regulation. This has led to the delineation of several different types of Treg; major examples include T cells co-expressing CD4 and CD25 and T cells producing large amounts of IL-10 and TGFBETA.
Our laboratory focuses on the characterisation of these and recently identified novel populations of Tregs in the context of islet autoimmunity to answer the following questions:
1. What mechanisms are involved in regulating potentially pathogenic T cells?
2. Are these mechanisms deficient in individuals with T1DM?
These studies will promote our understanding of the immune processes that lead to pathological islet autoimmunity, and enable the development of tools to promote the study of a third question, namely:
3. Can regulatory mechanisms can be promoted in diabetes-prone or islet transplanted individuals through immunotherapeutic interventions?
The approach of our laboratory has been to focus on human, islet-specific immune regulation. In doing so, we have identified a functional defect in the population of Tregs identified by co-expression of CD4 and CD25 in individuals with T1DM and uncovered two hitherto undefined T-reg populations of importance to this field namely; islet specific IL-10+ Tregs and HLA-DQ restricted insulin specific Tregs.
Associated research programmes
Associated staff research interests
Interests:
As a post-doctoral fellow with Susumu Tonegawa at MIT, I contributed to the molecular cloning and characterisation of translocated c-myc genes in human Burkitt's lymphoma, and to the T cell receptor (TCR) genes. This included the unanticipated identification of the TCR gamma chain, which was followed by the discovery of the hitherto unknown gamma delta T cells. Assuming an independent Faculty position at Yale, I adopted molecular genetic approaches, including the development of key gene knockout and transgenic models, to elucidate gamma delta T cell function and development.
Those studies collectively have illuminated several areas, including:
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).
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Interests:
Primary interest: B cell repertoire analysis, and molecular events involving the immunoglobulin gene during B cell development. Combining traditional molecular biology techniques with novel mathematical analyses to devise new ways of investigating the humoral immune system.
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.
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.
Tel:
020 7188 3058
Email:
Website:
Interests:
The CMCBI was recently established in new laboratory space in King's College London (Division of Immunology, Infection and Inflammatory Diseases) with the support of the Arthritis Research Campaign (arc).
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.
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.
Tel:
020 7848 6902
Fax:
0207 848 6743
Email:
Website:
Interests:
Mucosal immunology and development.
Email:
Website:
Interests:
Using (and developing in collaboration with physicists and engineers) cutting-edge microscopy techniques to investigate the molecular mechanisms of patolling monocytes in context
Defining the molecular interactions and signalling events at the monocyte and endothelial cell interface in vivo
Interests:
Molecular and cellular basis of HIV vaccine development; innate immunity and regulation of dendritic cell function; gene therapy development in models of rheumatoid arthritis.
Tel:
020 7188 0151
Email:
Website:
Interests:
The activity of T cells is tightly controlled to ensure that effective immune responses can be elicited, whilst pathological inflammatory disorders are prevented. Numerous signals from cell-bound and soluble ligands influence the fate of T cells, and these need to be correctly relayed along multiple signalling pathways. We are interested in understanding the players and processes involved in these complex molecular networks. In particular, my lab focuses on the regulation of protein functions by posttranslational modifications through which we aim to gain insights into basic biological processes and to elucidate novel aspects of T cell regulation.
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.
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.
Tel:
020 7188 3060
Email:
Website:
Interests:
Type 1 diabetes; T lymphocyte function; endocrine autoimmunity; immunotherapy.
Tel:
020 7188 0148
Fax:
020 7188 3385
Email:
Website:
Interests:
Our background is in viral recognition by dendritic cells and we have studied dendritic cell activation via several pattern recognition receptors in the past. The main viral pathogen-associated molecular patterns that are recognised by the innate immune system are viral nucleic acids and there are cytoplasmic and endosomal pattern recognition receptors with the ability to sense viral single-stranded RNA, viral double-stranded RNA and viral DNA. Dendritic cells are not the only cells expressing these pattern recognition receptors, but because of their crucial role in the instruction of adaptive immune responses, the mechanisms of their activation is of particular importance.
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.
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.
Tel:
020 7188 1181
Fax:
020 7188 3385
Email:
Website:
Interests:
Cytokines are potent mediators of cell-cell communication, whose expression and functions are tightly regulated at the level of magnitude and duration, by transcriptional and post-translational mechanisms. Upon binding to their cognate receptors, virtually all cytokines signal by activating the evolutionarily conserved JAK-STAT signalling pathway leading to regulation of diverse cellular functions ranging from embryonic stem cell renewal to regulation of the immune system. There are four Janus activated Kinases (JAK1-3 and Tyk2) and seven signal transducers and activators of transcription proteins (STAT1-4, 5a, 5b and 6).
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.
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.
Tel:
020 7188 3071
Fax:
0207-188-3385
Email:
Website:
Interests:
Role of autoreactive and regulatory T cells in human health, disease and transplantation. Developing statergies to strengthen immune regulation.
Tel:
020 7188 1182
Fax:
020 7188 3385
Email:
Website:
CONTACTS FOR FURTHER INFORMATION
Suzanne Creighton
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