1.Lymphoid stress-surveillance: from concept to clinic
2. The Development of Innate-Like T cells
Pierre Vantourout, Vassia Sofra, Rick Wolf, Bodhi Hunt, Stathis Theodoridis
Lymphocytes are traditionally assigned to the antigen-specific adaptive response that takes some time to develop but which can provide long-term memory. However, our work has identified and focussed on compartments of T cells that reside at steady-state within tissues and that respond rapidly to challenges, in synchrony with innate immunity. Our research investigates the functional potential of such “Lymphoid Stress-Surveillance”, and identifies the scenarios in which it is most active. In this regard skin lymphoid stress surveillance appears to be a key regulator of skin graft rejection via a molecule, NKG2D, that is upregulated by tissue dysregulation via mRNA stabilisation. Unexpectedly, NKG2D-dependent T cell activation rapidly provoked lgE syntheiss, thereby establishing a novel link between tissue stress and atropy that we are currently investigating.
3. Lymphoid Stress Surveillance of Cancer
Melanie Wencker, Anett Jandke, Livija Deban, Rosie Hart, Rafael di Marco Barros, Martin Woodward
It has recently become clear from our own, our collaborators’ and others’ work that gamma delta T cells can generate pro-inflammatory effector responses, such as IL-17 and interferon-gamma, far more quickly than can conventional alpha beta T cells. This capacity is laid down during development in the thymus, and it forms a key component of composing a rapid, stress-surveillance response pathway. However, the nature of the molecular engagements in the thymus that may determine this is very poorly understood. To distinguish the roles of some leading candidates that include ligands for the T cell receptor; CD27; and the Lymphotoxin receptor, we are combining the use of thymic organ culture with novel gain-of-function and loss-of-function systems. A major advance in characterising innate-like T cell development was the identification by us and our collaborators of Skint 1, the first genetic determinant of γδ cell development that is required for formation of the murine epidermal T lymphcyte compartment. Skint 1 is expressed exclusively by epithelial cells and its understanding is providing radical new insights into the regulation of T cells by epithelial cells.
4. Generation of an open-source library of mouse knockout immunophenotyping data by the 3i consortium
Fernanda Kyle, Deborah Enting, Marialuisa Iannitto, Yin Wu, Oliver Nussbaumer
There is a surging tide of interest in the prospect of tumour immunotherapy, motivated at least in part by striking efficacies of newly introduced immuno-therapeutics such as ipilimumab. A conspicious group in our understanding is the specificity and properties of tumour-reactive T cells that are activated by such immunotherapies. In particular, we ask whether lymphoid stress-surveillance mechanisms are operative. To this end, primary T cells are harvested from human tumour explants using a novel cyto-protective protocol and their response modes and specificities assessed. The phenotypes and response-modes of human peripheral blood lymphocytes are also assessed in patients in relation to disease and treatment regimens. By the integration of these approaches, we seek to define tumour-reactive T cells; conditions that promote them; and bio-markers for their beneficial effects in patients as they relate to clinical treatment decisions.
5. Human Immune Response Dynamics (HIRD)
Adam Laing, Dmitry Ushakov, Namita Saran, Keng Hng, Susana Caetano, Lucie Abeler-Dörner
The Infection and Immunity Immunophenotyping (3i) consortium has been formed to conduct a high-throughput immunological phenotyping of approximately 800- 1000 knockout mouse lines generated by the Wellcome Trust Sanger Institute (WTSI) between 2013 and 2018. Funded by the Wellcome Trust and led by King’s College London, the project includes participants from WTSI, Imperial College, and the Universities of Oxford, Cambridge, and Manchester.
The phenotyping has two components, an observational screen and a challenge screen. In the observational screen the immune cell compartments of different lymphoid and non-lyphoid organs are analysed in order to identify genes regulating the immune system at steady state. The challenge screen looks at responses to chemical stress and to viral and bacterial infections that collectively mimic major aspects of human exposure to the environment and that therefore permit the likely identification of genes that regulate the human immune response under challenge. The mechanism of action of such genes is explored in follow-up studies, in our laboratory and in collaboration with the community.
The team at KCL is responsible immunophenotyping the lymphocyte compartments of spleen, lymph nodes and bone marrow by flow cytometry and to analyse the immune compartment in the skin by fluorescent microscopy.
The project makes use of state-of-the-art multicolour flow cytometry and fluorescent microscopy and employs cutting-edge tools for automated data analysis and dissemination. All generated data is open source and available to the scientific community whose involvement will be encouraged by the programme’s outreach component. To learn more, look at results and check the status of your favourite genes, please visit the consortium’s webpage.
Olga Sobolev, Sean O’Farrell
Although the molecules and cells that are key to immune function are well understood, there is little appreciation of how their effects are integrated to human immune responses. To this end we have established the logistical platform to support human immune monitoring and have described the innate and adaptive responses to swine flu vaccination in our model systems, together with project area 5.