Quantitative modelling of T cell activation and co-stimulation

Thesis

Precisely regulated activity of T cells is crucial to effectively control pathogens while limiting immunopathology to a minimum. Even though T cell activation is predominantly governed by antigen recognition through the T cell receptor (TCR), the activity of an array of various accessory receptors can markedly alter this decision-making process, with the potential to serve as attractive therapeutic intervention points. Therefore, many of these co-stimulatory and co-inhibitory receptors and their molecular signalling pathways have been characterised. However, how exactly these receptors integrate with TCR signalling to affect the T cell response quantitatively remains poorly understood.

Here, we used in vitro expanded primary human T cells in a minimal stimulation platform to study co-stimulation through receptors of the TNF receptor superfamily (TNFRSF) in isolation. This allowed us to precisely define the ligand doses and stimulation times in order to capture the quantitative effects of TNFRSF signalling on the T cell cytokine response, with a particular focus on two representative TNFRSF members, 4-1BB and CD27. We found that 4-1BB costimulation was able to prolong the cytokine response, while engagement of CD27 increased the amount of cytokine produced without affecting the duration of the response and the T cells still became unresponsive after 8 hours. However, in combination with computational modelling, detailed analysis of our results showed that the distinct phenotypes of these receptors were mainly caused by their differential expression pattern in time, while the TNFRSF members share a common co-stimulatory mechanism, which we summarised in a minimal mathematical model. Simulations of the model predicted that co-stimulation through either of 4-1BB and CD27 could rescue TCR-dependent cytokine production in T cells which had become unresponsive through previous stimulation, and that CD27 could increase the potency of 4-1BB by enhancing its expression. We were then able to validate the model by confirming the both the rescue of the response and the synergy between TNFRSF members experimentally.

Authors: Nguyen, J

• DOI: 10.5287/ora-bmmg9jrrk
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: tumour necrosis factor receptor superfamily; T cell co-stimulation; 4-1BB; T cell signalling; T lymphocytes; CD27
• Subjects: immunology; T cells