Investigating the temporally dynamic mechanisms of T-cell regulation during helminth infection

Tolerance mechanisms are vital for maintaining immune homeostasis in the intestinal system. The intestinal system must remain primed against pathogens whilst nutrients are absorbed without an inappropriate inflammatory response. Regulatory T-cells (Treg) are a key cell type for maintaining tolerance, primarily acting to suppress inflammatory T-cell responses. This mechanism is exploited by helminth parasites, including Heligmosomoides polygyrus (H. polygyrus), in order to suppress the anti-helminth T-cell response and establish chronic infection. H. polygyrus infection therefore provides a useful model for studying the dynamics of T-cell regulation in vivo. The current understanding of T-cell and Treg dynamics in vivo is limited. This thesis uses the novel Timer Of Cell Kinetics and Activity (Tocky) reporter system developed by the Ono Lab to overcome this knowledge-gap. Tocky reveals whether a gene of interest is actively transcribed or has previously been transcribed in real-time. Here, Foxp3-Tocky mice are used to report transcription of the key Treg gene Foxp3, and Nr4a3-Tocky mice are used to reveal T-cell receptor signalling through transcription of the Nr4a3 gene. This thesis identifies that during early primary H. polygyrus infection, a proportion of infection-reactive T-cells appear to induce and maintain Foxp3 transcription. Further analyses, including transcriptomic analysis, support that activated T-cells are a source of Treg in this context. Within secondary infection, where mice exhibit resistance to re-infection, Foxp3 transcription within Treg appears to be very similar to that in primary infection. However, the Treg pool is offset by the memory T-cell pool. In conclusion, I demonstrate that a subset of T-cells activated in H. polygyrus infection up-regulate Foxp3 transcription, potentially as a mechanism to suppress their own anti-parasite T-cell response. In secondary infection, Foxp3 transcription is similarly initiated and maintained, however, due to disproportionate expansion of the memory T-cell population, the Treg response is ineffective.Open Acces