About our research interests
1. Manipulating the balance between regulatory and effector/pathogenic T cells - implications for disease processes (SFI project).
The Th1-Th2 model provided a useful basis for our understanding of the mechanisms of immunity to infection and the role of immune responses in autoimmunity and allergy. However, this paradigm has recently shifted following the discovery of further subtypes of T cells. Regulatory T (Treg) cells help to control immune responses to self-antigens, thereby preventing autoimmunity, but also limit collateral damage during immune responses to pathogens. Furthermore, the pathology in certain autoimmune diseases appears to be mediated, not by Th1 cells, but a distinct population of T cell, that secrete IL-17, termed Th17 cells. Th17 cells may also play a role in protection or immunopathology during infection. My current SFI programme grant will examine the hypothesis that immune homeostasis is dependent on balance between regulatory and effector/pathogenic T cells and manipulating this balance may be a promising approach for the treatment of diseases with an immunological basis. The aims are to examine the balance between Th17 and Treg cells, and the consequences of its disruption, in mouse models of infection, hitherto considered to be dominated by Th1 or Th2 cells. We are studying the factors that control the induction of Treg and Th17 cells, especially the role of innate cytokines. This information will be used to design approaches for selective activation of Treg cells, and how this can inhibit Th17 cells that mediated autoimmunity, or for selective inhibition of Treg cells, and how this can be used to enhance effector Th1 cells and thereby develop more effective immunotherapeutic and vaccines against infection or cancer.
2. Pathogen Modulation of Immune Responses
The innate immune response provides the first line of defence against infection and instructs the T and B cells of the adaptive immune response. Binding of conserved pathogen-derived molecules to pattern recognition receptors (PRRs), including members of the IL-1/Toll-like receptor family on innate cells, such as dendritic cells (DC), activates signalling pathways, which results in the transcription of a number of immune response genes that enhance antigen presentation and the development of T cell responses. Binding of immunomodulatory molecules (IMs) from different families of pathogens to PRRs activates distinct DC subtypes, which selectively stimulate distinct T helper cell subtypes, including Th1, Th2 and Th17 cells. These immune responses must be tightly regulated, as inappropriate or unchecked responses can exacerbate infection, or lead to excess inflammation or immunopathology. Furthermore, pathogens have evolved strategies to subvert protective immunity, by inducing regulatory T cells, inhibitory cytokines, or directly modulating signalling and function of T cells or antigen presenting cells.
The aim of our research is to examine the role of pathogen-derived molecules in modulating immune responses, with particular reference to the induction, regulation and function of T cell subtypes and the induction and control of inflammatory responses. Our hypothesis is that the study of immunomodulation by microbial pathogens is an ideal approach to understand mechanisms of protective immunity and immunoregulation in vivo and will allow the identification of novel IMs with critical immunoregulatory functions. This project has already identified IMs capable of specifically enhancing or suppressing distinct arms of the immune response that resolve or mediate a number of diseases. This has allowed us to develop novel approaches for the development of immunotherapeutics against autoimmunity, and vaccines against infection and cancer.
3. Immunity to Infectious Diseases and Vaccines
We have a number of projects focused on increasing our understanding of the mechanisms of protective immunity against infectious pathogens. A major goal of our research has been to develop a better understanding of the factors that affect the induction of Th1, Th2, Th17 and Treg cells, and the role of innate immune system, in particular dendritic cells, in directing T cell responses. The work on Bordetella pertussis has been successful in defining mechanisms of immune protection against this respiratory pathogen. Our work has direct application to the development of new or improved vaccines against several infectious diseases, including pertussis, diphtheria, meningococcus B, influenza virus, TB and hepatitis C virus.
4. Tumor Immunology
Our work on Treg cells lead us to examine the role of these cells in subverting anti-tumor immunity. We have shown that IL-10 and TFG- b secreting T cells are recruited into tumors and that depletion of Treg cells allow the generation of anti-tumor immunity and prolong survival in murine models. We are also working on tumor vaccines, either by direct immunization or in the form of modulated dendritic cells. The aim here is to develop anti-tumor vaccine or therapies based on inhibiting Treg cells and inducing effector T cells.
We are interested in the role of T cells and inflammatory cytokines in infection induced neuro-inflammation and in neurodegenerative conditions. A recent focus has been the role of pathogenic versus Treg cells in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. We have a collaborative project with Dr Niall Tubridy, Consultant Neurologist, at St Vincent’s Hospital looking at the role of pathogenic IL-17-secreting T cells and Treg cells in multiple sclerosis patients. In collaboration with Prof Marina Lynch at the TCD Institute for Neuroscience (TCIN), we are examining the role of T cells and inflammatory responses in the brain in models of neurodegeneration and Alzheimer's disease. Finally, we have a collaborative project with Dr Tom Connor, TCIN on the role of IL-10 in stress-induced inflammation.