New evidence that B cells produce the well-known 3B lineage cellsMonocytesB cell-deficiency orB cell-specific GABA synthesisenzyme deletionAnti-inflammatorymacrophagesCytotoxic T cellsPro-inflammatorymacrophagesArginase 1 IL-10Cytotoxic factorsTNF-aTumourcellgrowthTumourcelldeathGABAHirano T, Shiroguchi K, Matsuda F, Suematsu M, Honjo T, Fagarasan S. B cell-derived GABA elicits IL-10+ macrophages to limit anti-tumour immunity. Nature 599, 471-476 (2021) doi: 10.1038/s41586-021-04082-1neurotransmitter GABA suggests there may be an-other mode of communication in the immune system.Ever since life began, singled-celled organisms like bac-teria have used cues in their environment to grow, com-municate and survive. These signals often take the form of metabolites, small water-soluble molecules produced as cells break down larger compounds. While we know that some multicellular processes also sense and exchange information through metabolites, the details and extent of this mechanism in mammals are just beginning to be un-earthed.Recent work from Sidonia Fagarasan, Team Leader of the Laboratory for Mucosal Immunity at IMS, and her group suggests that metabolites may play a role in the mammalian immune system. “We discovered that activa-tion of the immune system changes the metabolome pro-foundly,” she said, implying that immune cells are consum-ing and utilising metabolites.Fagarasan hypothesized that, like the classic system of cytokines and receptors, metabolites may act as a mode of communication. In a new study published in Nature, her team took a multidisciplinary approach, combining immu-nology with biochemistry and metabolomics, to identify these molecules and their roles.The researchers first inoculated mice to activate the immune system and compared the profiles of over 200 me-tabolites in activated and non-activated lymph nodes from the same animals. In complementary studies, they also compared compounds produced in mice lacking T cells, B cells, or both. To their surprise, they discovered that B cells produced GABA-a well-known inhibitory brain chemical.To probe the function of this metabolite in the immune system, the team took the first ever look at its effect on tumours. When they implanted a GABA-releasing pellet into a mouse cancer model lacking B cells, the group found that tumour growth accelerated, suggesting that, like in the brain, GABA may play a suppressive role in the immune system.Indeed, the team went on to show that GABA promoted the development of macrophages that produce the typical anti-inflammatory cytokine IL-10, but inhibited expression of the pro-inflammatory molecule TNF-alpha. GABA also inhibited “killer” T cells, which normally destroy tumours.“I think the GABA produced by B cells is educating macrophages to become anti-inflammatory,” Faragasan said. She added that while this is beneficial for the normal repair of tissues, it could be harmful when a more active immune response is required, such as in the presence of a tumour.According to Fagarasan, we may have inherited this metabolite communication method from our simpler an-cestors, noting that bacteria and plants produce GABA as a signalling molecule. However, to truly appreciate how and why GABA is being used in the mammalian immune sys-tem, the next step is to uncover the modus operandi.“If we understand how the cells are working and com-municating, then we can turn on and off that dialogue,” Fagarasan said, a feat that could open the door to novel treatments.Figure: B cells produce GABA, whose “calming” effect accelerates tumour growth(Top) GABA generated by B cells promotes the develop-ment of macrophages that secrete the anti-inflammatory cytokine IL-10. IL-10 in turn inhibits cytotoxic “killer” T cells, whose role is normally to destroy tumour cells, lead-ing to rapid tumour growth.(Bottom) In the absence of GABA, macrophages that produce pro-inflammatory molecules such as TNF-alpha dominate. TNF-alpha in turn activates the destruction of tumour cells via T cell activity, leading to tumour death.Original paper:Zhang B, Vogelzang A, Miyajima M, Sugiura Y, Wu Y, Chamoto K, Nakano R, Hatae R, Menzies RJ, Sonomura K, Hojo N, Ogawa T, Ko-bayashi W, Tsutsui Y, Yamamoto S, Maruya M, Narushima S, Suzuki K, Sugiya H, Murakami K, Hashimoto M, Ueno H, Kobayashi T, Ito K, Sidonia FagarasanBrain chemical plays immune modulator
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