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Title: Environmental stimuli shape adaptive immunity by enhancing T helper cell differentiation and the germinal centre response
Author: Stebegg, Marisa
ISNI:       0000 0004 7968 4598
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2019
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Immune cells have evolved to respond to external danger signals and to incorporate information about environmental cues to adapt their differentiation and effector function. Because of this, it is important that immune cells are studied in the context of their surroundings. In this thesis, I investigated the roles of environmental endoplasmic reticulum (ER) stress, the gut microbiome and ageing on adaptive immunity. Immune cells have been shown to integrate inflammatory signalling with the ER stress response pathway. This response is triggered by a variety of environmental stresses such as low nutrient availability, hypoxia and mechanical stress. I found that the ER stress response acts as a potent driver of T helper 17 (Th17) cell differentiation resulting in Th17 cells with a pathogenic gene expression signature. This suggests a link between ER stress-inducing conditions such as low nutrient availability, and the pathology of Th17 cell-mediated autoimmune diseases. Another physiological scenario in which the immune microenvironment changes is during ageing. Ageing-related changes of the gut microbiome have recently been linked to increased frailty and systemic inflammation. This change in microbial composition with age occurs in parallel with a decline in function of the gut immune system, however it is not clear if there is a causal link between the two. Here, I establish that the defective germinal centre (GC) reaction in Peyer's patches in the small intestine of aged mice can be rescued by co-housing of adult and aged mice, and via faecal transfers from adult into aged mice. This demonstrates that the poor GC reaction in aged animals is not irreversible, and that it is possible to improve immune responses in older individuals by replenishing the gut microbiome. To determine whether GC responses can also be improved in peripheral lymph nodes, we investigated the role of defective helper T cell priming in aged mice. We observed that the age-associated defect in the GC reaction is partly due to impaired T cell priming by dendritic cells (DCs). By boosting type I interferon signalling in DCs at the time of immunisation, I was able to improve T cell priming and GC formation in aged mice. This demonstrates that not only the gut microbiome, but also DCs are exciting targets to improve GC responses in ageing and highlights the importance of environmental stimuli in shaping adaptive immunity.
Supervisor: Linterman, Michelle Sponsor: EU
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: germinal centre (GC) ; T follicular helper (Tfh) cell ; dendritic cell ; ageing ; gut microbiome ; Peyer's patch ; T helper 17 (Th17) cell ; endoplasmic reticulum stress