Phenotypic models of T cell activation

• Main Author: Lever, Melissa
• Other Authors: Dushek, Omer ; Maini, Philip
• Published: University of Oxford 2015
• Subjects: 616.07
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.719900

T cells are important immune cells that initiate and regulate immune responses to cell surface antigens. The productive binding of T cell receptors (TCRs) to cell surface antigens initiates a signal transduction cascade within the T cell that results in T cell effector functions. It is established that the dose of antigen and the binding parameters between TCRs and antigen determines the functional response of the T cell. Although much progress has been made to identify the molecules that constitute the intracellular signalling network, it remains unclear how these molecules interact with each other to convert antigen concentration and binding paramters into a downstream response. A mathematical model of T cell activation can provide insight into this network, however despite extensive study, there is still no conclusive model. We have taken a phenotypic modelling approach to study T cell signalling. We begin by reformulating the existing models of T cell activation in the literature under a consistent framework so that they can be categorised. This analysis reveals that detailed, quantitative studies of T cell activation are required to test the models. We address this by using a high affinity T cell receptor system to generate dose-response data. The antigens have a 105 range in affinity for the TCR and are presented over a very wide range of concentrations. The dose-response assays show that there is an optimal affinity at low antigen dose, and the dose-response profiles can be seen to decrease at high antigen doses. We then generate simple a model that can exhibit these phenotypes, which we term the kinetic proofreading with limited signalling coupled to an incoherent feed forward motif model. The structure of this model has implications for the structure of the T cell signalling network. The model indicates that there is a mechanism that causes activated TCRs to become inert on a timescale of around ten minutes, which we attribute to their internalisation and down-modulation. The incoherent feed forward motif suggests two parallel inhibitory and activatory pathways within the T cell that both act on a downstream molecule. Further research must be done to identify the molecules involved in this motif.