B cell-derived GABA elicits IL-10+ macrophages to limit anti-tumour immunity

作者：Baihao Zhang, Alexis Vogelzang, Michio Miyajima, Yuki Sugiura, Yibo Wu, Kenji Chamoto, Rei Nakano, Ryusuke Hatae, Rosemary J. Menzies, Kazuhiro Sonomura, Nozomi Hojo, Taisaku Ogawa, Wakana Kobayashi, Yumi Tsutsui, Sachiko Yamamoto, Mikako Maruya, Seiko Narushima, Keiichiro Suzuki, Hiroshi Sugiya, Kosaku Murakami, Motomu Hashimoto, Hideki Ueno, Takashi Kobayashi, Katsuhiro Ito, T Hirano, Katsuyuki Shiroguchi, Fumihiko Matsuda, Makoto Suematsu, Tasuku Honjo, Sidonia Fagarasan · 发表于：Nature · 年份：2021 · DOI：10.1038/s41586-021-04082-1 · 被引用次数：466 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Tryptophan and brain disorders、Immune Cell Function and Interaction

Abstract Small, soluble metabolites not only are essential intermediates in intracellular biochemical processes, but can also influence neighbouring cells when released into the extracellular milieu 1–3 . Here we identify the metabolite and neurotransmitter GABA as a candidate signalling molecule synthesized and secreted by activated B cells and plasma cells. We show that B cell-derived GABA promotes monocyte differentiation into anti-inflammatory macrophages that secrete interleukin-10 and inhibit CD8 + T cell killer function. In mice, B cell deficiency or B cell-specific inactivation of the GABA-generating enzyme GAD67 enhances anti-tumour responses. Our study reveals that, in addition to cytokines and membrane proteins, small metabolites derived from B-lineage cells have immunoregulatory functions, which may be pharmaceutical targets allowing fine-tuning of immune responses.