Rosser, EC;
(2014)
Essential role for inflammatory signals in the differentiation and function of regulatory B cells.
Doctoral thesis , UCL (University College London).
Abstract
Regulatory B cells (Bregs), identified by this laboratory as transitional-2 marginal zone precursor cells (T2-MZPs), restrain immune-driven diseases by inhibiting pathogenic T cell differentiation via the provision of IL-10. Despite intense investigation into their effector function, little is known regarding the cellular processes that govern Breg differentiation. Here I show that arthritic inflammation controlled by the gut-microflora promotes the differentiation of splenic Bregs. Drastic alteration of the inflammatory process imposed by anti-TNFα treatment or changes in the gut-microflora caused a deficiency in the production of IL-1β and IL-6, and concurrently in the number and functional capacity of Bregs. Furthermore, Bregs induced by IL-1β and IL-6 were critical in limiting excessive inflammatory responses, as disruption of IL-1R1 and IL-6R exclusively on B cells lead to the development of an exacerbated arthritis and reduced IL-10 production by splenic B cells. These results led to the question of how the gut-microflora influences the differentiation of splenic-Bregs? I found that splenic-T2-MZPs, expressed the gut-homing marker α4β7, and were also detectable in the mesenteric lymph nodes (MLN). Furthermore, similarly to the spleen, changes imposed on the microbiome by antibiotics treatment caused a reduction in both the number of IL-6+ cells and IL-10+Bregs in the MLN. Interestingly, further analysis revealed that MLN-T2-MZPs were not exposed to IL-1β in the MLN and were only-partially suppressive when compared to their splenic counterparts. Collectively, this data suggests a possible scenario where Breg differentiation is initiated in the MLN following exposure to gut-microbiota induced IL-6, but B cells do not become fully-committed Bregs until exposure to the combination of both IL-1β and IL-6 in the spleen.
| Type: | Thesis (Doctoral) |
|---|---|
| Title: | Essential role for inflammatory signals in the differentiation and function of regulatory B cells |
| Language: | English |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1448074 |
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