This Work Package requires a combination of novel experimental techniques and modelling (deterministic and stochastic) approaches, and thus mathematicians (B1, B2, B8) and experimental immunologists (B5 and B8) will work closely together. The main objective is to quantify whole body compartmentalisation and kinetic rates of naive and memory T cells and develop suitable mathematical models.
Work Package 1 requires a combination of novel experimental techniques and modelling (deterministic and stochastic) approaches, and thus mathematicians (B1, B2, B8) and experimental immunologists (B5 and B8) will work closely together.
ESR1 and ESR2 will quantify and perturb the competition between thymic progenitor cells (thymocytes) to define its molecular and cellular basis. To this end, ESR1 will employ a mouse model previously developed at DKFZ (B8) that allows hematopoietic stem-cell transplantation without irradiation, thus enabling to switch hematopoiesis from stem-cells competent for lymphoid development (i.e., normal thymus function) to genetically modified stem-cells that cannot produce lymphocytes (i.e., resulting in thymus autonomy). This mouse model will allow ESR1 to generate hematopoietic fate-mapping data. ESR2 will make use of ordinary differential equations (ODEs), stochastic birth and death processes, parameter identification methods and the data generated by ESR1 to develop a quantitative model of thymocyte development.
ESR3 will develop stochastic mathematical models to understand the molecular mechanisms and receptor-mediated signals that regulate the long-term maintenance of naive T cells in lymphoid tissues. ESR3 will make use of data from Farber (visiting scientist) and will generalise stochastic models developed at Leeds to include TCR, IL-7R and CD28 signalling.
ESR4 and ESR5 will study the dynamics of memory T cells making use of in vivo deuterium labelling, the most powerful technique that is currently available (in only a few laboratories worldwide) to quantify the longevity and proliferative behaviour of T cells. UMCU (B5) has extensive experience with this method. ESR4 will be trained in its use given its advantages: it is non-toxic and can safely be applied to humans, it does not interfere with cell dynamics, it is incorporated into dividing cells whenever and wherever they divide (which is important when analysing the dynamics of T cells that may recirculate), and it can be fairly compared between different sites of the body. ESR4 will make use of this technique to study for the first time the dynamics of T cells in human bone marrow. ESR5 will model deuterium labelling data by means of ODEs to determine the rate of proliferation and lifespans of different T cell populations.
ESR6 will make use of stochastic compartmental birth, death and migration models to study whole body naive and memory T cell maintenance. ESR6 will also make use of data from Farber (visiting scientist) and Bayesian methods to carry out model selection and parameter inference.