Regulatory B cells are critical for controlling immune and inflammatory responses. Whilst a number of effector mechanisms have been described, it is thought that they predominantly exert this function through the release of IL-10. This suppressive capacity has been well highlighted in murine models of disease, whereby loss of regulatory B cells results in exacerbated inflammation. Conversely, adoptive transfer can limit onset and severity of inflammatory disease. Broadly similar findings have been observed in human regulatory B cells, albeit defined by their function in vitro. Whilst important observations have defined certain populations as enriched producers of IL-10 in both systems, there is currently no identifying lineage marker equivalent to that seen in FOXP3+ regulatory T cells. Therefore, efforts to understand regulatory B cell biology have primarily focussed around IL-10 production as a defining feature. With regards to the induction of IL-10 in human B cells, TLR9 or CD40 engagement appear to be important. However, the molecular mechanisms underpinning this regulatory phenotype are not well understood. Here cholesterol metabolism is defined as a critical pathway for the induction of a regulatory phenotype, through its control of IL-10. Mechanistically, the pathway metabolite geranylgeranyl pyrophosphate, is identified to regulate IL-10 production through its control of TLR9-Ras-PI3K-AKT-GSK3 signalling, which culminates in BLIMP1-dependent expression of IL-10. These in vitro findings displayed a similarity to patients with dysregulated cholesterol metabolism, specifically mevalonate kinase deficiency (MKD), who develop severe systemic inflammation alongside elevated serum immunoglobulins. Here it is shown that B cells from these patients do not induce an effective regulatory phenotype, defined by impaired IL-10 production, and an inability to suppress inflammatory T cell responses. Furthermore, unlike in healthy donors who produce sufficient levels, supplementation of geranylgeranyl pyrophosphate to MKD B cells is able to rescue IL-10 production. The contribution of regulatory B cells in restricting inappropriate cellular and humoral responses may therefore explain, at least in part, the inflammatory nature of these patients. Collectively, these data demonstrate cholesterol metabolism as a central pathway for the induction of a regulatory phenotype in human B cells.
Cholesterol metabolism drives regulatory B cell function
Bibby, J. (Author). 1 Nov 2019
Student thesis: Doctoral Thesis › Doctor of Philosophy