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 Murakami, Motomu Hashimoto, Hideki Ueno, Takashi Kobayashi, Katsuhiro Ito, Tomoko Hirano, Katsuyuki Shiroguchi, Fumihiko Matsuda, Makoto Suematsu, Tasuku Honjo and Sidonia Fagarasan ()
Additional contact information
Baihao Zhang: RIKEN Yokohama Institute
Alexis Vogelzang: RIKEN Yokohama Institute
Michio Miyajima: RIKEN Yokohama Institute
Yuki Sugiura: Keio University
Yibo Wu: RIKEN Yokohama Institute
Kenji Chamoto: Kyoto University Graduate School of Medicine, Kyoto University
Rei Nakano: Nihon University College of Bioresource Sciences
Ryusuke Hatae: Kyoto University Graduate School of Medicine, Kyoto University
Rosemary J. Menzies: Kyoto University Graduate School of Medicine, Kyoto University
Kazuhiro Sonomura: Kyoto University Graduate School of Medicine, Kyoto University
Nozomi Hojo: RIKEN Center for Biosystems Dynamics Research (BDR)
Taisaku Ogawa: RIKEN Center for Biosystems Dynamics Research (BDR)
Wakana Kobayashi: RIKEN Yokohama Institute
Yumi Tsutsui: RIKEN Yokohama Institute
Sachiko Yamamoto: RIKEN Yokohama Institute
Mikako Maruya: RIKEN Yokohama Institute
Seiko Narushima: RIKEN Yokohama Institute
Keiichiro Suzuki: RIKEN Yokohama Institute
Hiroshi Sugiya: Nihon University College of Bioresource Sciences
Kosaku Murakami: Kyoto University Graduate School of Medicine, Kyoto University
Motomu Hashimoto: Kyoto University Graduate School of Medicine, Kyoto University
Hideki Ueno: Kyoto University Graduate School of Medicine, Kyoto University
Takashi Kobayashi: Kyoto University Graduate School of Medicine, Kyoto University
Katsuhiro Ito: Kyoto University Graduate School of Medicine, Kyoto University
Tomoko Hirano: Kyoto University Graduate School of Medicine, Kyoto University
Katsuyuki Shiroguchi: RIKEN Center for Biosystems Dynamics Research (BDR)
Fumihiko Matsuda: Kyoto University Graduate School of Medicine, Kyoto University
Makoto Suematsu: Keio University
Tasuku Honjo: Kyoto University Graduate School of Medicine, Kyoto University
Sidonia Fagarasan: RIKEN Yokohama Institute

Nature, 2021, vol. 599, issue 7885, 471-476

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-04082-1

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