Environmental stimuli shape adaptive immunity by enhancing T helper cell differentiation and the germinal centre response

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.PhD funding was provided by the EU-funded Horizon 2020 ENLIGHT-TEN project No. 675395 and additional consumables funding was provided by Marc Veldhoen and Michelle Linterman

Regulation of the Germinal Center Response

The germinal center (GC) is a specialized microstructure that forms in secondary lymphoid tissues, producing long-lived antibody secreting plasma cells and memory B cells, which can provide protection against reinfection. Within the GC, B cells undergo somatic mutation of the genes encoding their B cell receptors which, following successful selection, can lead to the emergence of B cell clones that bind antigen with high affinity. However, this mutation process can also be dangerous, as it can create autoreactive clones that can cause autoimmunity. Because of this, regulation of GC reactions is critical to ensure high affinity antibody production and to enforce self-tolerance by avoiding emergence of autoreactive B cell clones. A productive GC response requires the collaboration of multiple cell types. The stromal cell network orchestrates GC cell dynamics by controlling antigen delivery and cell trafficking. T follicular helper (Tfh) cells provide specialized help to GC B cells through cognate T-B cell interactions while Foxp3+ T follicular regulatory (Tfr) cells are key mediators of GC regulation. However, regulation of GC responses is not a simple outcome of Tfh/Tfr balance, but also involves the contribution of other cell types to modulate the GC microenvironment and to avoid autoimmunity. Thus, the regulation of the GC is complex, and occurs at multiple levels. In this review we outline recent developments in the biology of cell subsets involved in the regulation of GC reactions, in both secondary lymphoid tissues, and Peyer's patches (PPs). We discuss the mechanisms which enable the generation of potent protective humoral immunity whilst GC-derived autoimmunity is avoided

Rejuvenating conventional dendritic cells and T follicular helper cell formation after vaccination.

Germinal centres (GCs) are T follicular helper cell (Tfh)-dependent structures that form in response to vaccination, producing long-lived antibody secreting plasma cells and memory B cells that protect against subsequent infection. With advancing age the GC and Tfh cell response declines, resulting in impaired humoral immunity. We sought to discover what underpins the poor Tfh cell response in ageing and whether it is possible to correct it. Here, we demonstrate that older people and aged mice have impaired Tfh cell differentiation upon vaccination. This deficit is preceded by poor activation of conventional dendritic cells type 2 (cDC2) due to reduced type 1 interferon signalling. Importantly, the Tfh and cDC2 cell response can be boosted in aged mice by treatment with a TLR7 agonist. This demonstrates that age-associated defects in the cDC2 and Tfh cell response are not irreversible and can be enhanced to improve vaccine responses in older individuals