Kennedy Trust Prize Studentships
Spatial-temporal activation of immune responses by next generation vaccine adjuvants
- Project No: KTPS-NC-16
- Intake: 2021 KTPS-NC
Vaccines against complex disease pathologies including COVID-19, malaria, TB and cancer require innovative approaches requiring potent T cell responses including initiation of robust CTL responses. Although conventional adjuvants like alum can potently initiate robust TH2 antibody responses they fail to generate potent CTL responses required to initiate protective responses. During an immune response to a vaccine, orchestrated cellular activation and leukocyte migration promote rapid changes throughout the body, from the site of injection (SoI), secondary lymphoid organs such as the tissue draining lymph nodes (dLNs) and the spleen. This project will focus on a spatio-temporal requirements for adjuvant- and vaccine- induced changes at the injection site and draining lymphoid tissues using different priming routes. Key to the analysis of the overall cellular phenotype by multiparameter flow cytometry, multi-plex imaging and light sheet microscopy, and molecular events in selected cell types using a combination of single-cell RNA sequencing, RNAscope and spatial genomics to determine the underlying the innate events inducing efficacious CTL and CD4+ T cells immune cell responses. A particular focus will be on changes to the localised immune microenvironments including mechanisms driving stromal fibroblast and endothelial network remodelling and how the interactions between tissue resident macrophages with these different cell types drive the dynamics of the immune response. Through combing in vivo, imaging and genomics responses will provide a key platform to test and understanding methods to optimise induction of protective responses permitting translation of basic mechanisms of immune activation to impact on human disease.
Co-Supervisor 1: Professor Mark Coles (Kennedy Institute)
Co-Supervisor 2: Dr. Anita Milicic (Jenner Institute)
Co-supervisor 3: Dr. Calliope Dendrou (Wellcome Centre for Human Genetics)
Joint Supervisor(s): Sarah Davidson (Kennedy Institute)
The successful candidate will benefit from supervision by a team of scientists with key expertise in immunology, vaccine biology and spatial genomics. You will be based in the Kennedy Institute of Rheumatology, Jenner Institute and Wellcome Trust Centre of Human Genomics, world-leading centres in inflammatory biology, vaccines and genomics. The student will be able to take advantage of world leading technologies in the including spatial genomics, 10x, confocal/multiphoton microscopy, multi- Cell Dive imaging and 3D light sheet microscopy. obtain training in key cutting-edge technologies including 3D light sheet and multi-plex high dimensional imaging; spatial genomics and single cell data analysis; primary organ culture systems; immunological assays and mouse genetics. The Kennedy Institute has a vibrant PhD program with weekly journal club, seminars, student symposia, weekly internal institute presentations and training. Students at the Kennedy Institute have access to additional travel funding, training funding and paper completion funds at the end of their PhD.
- Cosgrove J, Novkovic M, Albrecht S, Pikor NB, Zhou Z , Onder L, Mörbe U, Cupovic J, Miller H, Alden K, Thuery A, O’Toole P, Pinter R, Jarrett S, Taylor E, Venetz D, Heller M, Uguccioni M, Legler DF, Lacey CJ, Coatesworth A, Polak WG, Cupedo T, Manoury B, Thelen M, Stein JV, Wolf M, Leake MC, Timmis J, Ludewig B, Coles MC, B-cell Zone Reticular Cell Microenvironments Shape CXCL13 Gradient Formation, Nature Communications, 2020, Jul 22;11(1):3677. doi: 10.1038/s41467-020-17135-2.
- Croft AP, Campos J, Jansen K, Turner JD, Marshall J, Attar M, Savary L, Perlman H, Barone F, McGettrick HM, Fearon DT, Wei K, Raychaudhuri S, Lorsunsky I, Brenner MB, Coles M, Sansom SN, Filer A, Buckley CD, Pathologically distinct fibroblast subsets drive inflammation and tissue damage in arthritis, Nature. 2019 Jun;570(7760):246-251. doi: 10.1038/s41586-019-1263-7
- Nayar S, Campos J, Smith CG, Iannizzotto V, Gardner DH, Mourcin F, Roulois D, Turner J, Sylvestre M, Asam S, Glaysher B, Bowman SJ, Fearon DT, Filer A, Tarte K, Luther SA, Fisher BA, Buckley CD, Coles MC, Barone F, Immunofibroblasts are pivotal drivers of tertiary lymphoid structure formation and local pathology. Proc Natl Acad Sci U S A. 2019 Jun 18. pii: 201905301. doi: 10.1073/pnas.1905301116.
- Reinke S, Thakur A, Gartlan C, Bezbradica JS, Milicic A. Inflammasome-Mediated Immunogenicity of Clinical and Experimental Vaccine Adjuvants. Vaccines (Basel). 2020 Sep 22;8(3):E554. doi: 10.3390/vaccines8030554.
- Dendrou CA, Petersen J, Rossjohn J, Fugger L. HLA variation and disease. Nat Rev Immunol. 2018 May;18(5):325-339. doi: 10.1038/nri.2017.143.
- Immune Microenvironments
- Systems biology
- Spatial Genomics
CONTACT INFORMATION OF ALL SUPERVISORS
Mark Coles, Kennedy Institute, University of Oxford