Published in:
European Journal of Immunology, 52 (2022) 3, Seite 418-430
Language:
English
DOI:
10.1002/eji.202149387
ISSN:
0014-2980;
1521-4141
Origination:
Footnote:
Description:
AbstractAlterations in cell metabolism can shift the differentiation of immune cells toward a regulatory or inflammatory phenotype, thus, opening up new therapeutic opportunities for immune‐related diseases. Indeed, growing knowledge on T‐ cell metabolism has revealed differences in the metabolic programs of suppressive Tregs as compared to inflammatory Th1 and Th17 cells. In addition to Tregs, IL‐10‐producing regulatory B cells are crucial for maintaining tolerance, inhibiting inflammation, and autoimmunity. Yet, the metabolic networks regulating diverse B‐lymphocyte responses are not well known. Here, we show that glutaminase blockade decreased downstream mTOR activation and attenuated IL‐10 secretion. Direct suppression of mTOR activity by rapamycin selectively impaired IL‐10 production by B cells whereas secretion was restored upon Glycogen synthase kinase 3 (GSK3) inhibition. Mechanistically, we found mTORC1 activation leads to GSK3 inhibition, identifying a key signalling pathway regulating IL‐10 secretion by B lymphocytes. Thus, our results identify glutaminolysis and the mTOR/GSK3 signalling axis, as critical regulators of the generation of IL‐10 producing B cells with regulatory functions.