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

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 MurakamiMotomu Hashimoto, Hideki Ueno, Takashi Kobayashi, Katsuhiro Ito, Tomoko Hirano, Katsuyuki Shiroguchi, Fumihiko Matsuda, Makoto Suematsu, Tasuku Honjo, Sidonia Fagarasan

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

Small, soluble metabolites not only are essential intermediates in intracellular biochemical processes, but can also influence neighbouring cells when released into the extracellular milieu1–3. 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.

Original languageEnglish
Pages (from-to)471-476
Number of pages6
JournalNature
Volume599
Issue number7885
DOIs
StatePublished - 18 Nov 2021
Externally publishedYes

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