TY - JOUR
T1 - B cell-derived GABA elicits IL-10+ macrophages to limit anti-tumour immunity
AU - Zhang, Baihao
AU - Vogelzang, Alexis
AU - Miyajima, Michio
AU - Sugiura, Yuki
AU - Wu, Yibo
AU - Chamoto, Kenji
AU - Nakano, Rei
AU - Hatae, Ryusuke
AU - Menzies, Rosemary J.
AU - Sonomura, Kazuhiro
AU - Hojo, Nozomi
AU - Ogawa, Taisaku
AU - Kobayashi, Wakana
AU - Tsutsui, Yumi
AU - Yamamoto, Sachiko
AU - Maruya, Mikako
AU - Narushima, Seiko
AU - Suzuki, Keiichiro
AU - Sugiya, Hiroshi
AU - Murakami, Kosaku
AU - Hashimoto, Motomu
AU - Ueno, Hideki
AU - Kobayashi, Takashi
AU - Ito, Katsuhiro
AU - Hirano, Tomoko
AU - Shiroguchi, Katsuyuki
AU - Matsuda, Fumihiko
AU - Suematsu, Makoto
AU - Honjo, Tasuku
AU - Fagarasan, Sidonia
N1 - Funding Information:
Acknowledgements We thank all members of the Fagarasan laboratory for discussions. We thank Y. Yanagawa (Gunma University) for Gad1fl/+ mice; M. Reth (University of Freiburg) and T. Kurosaki (IMS RIKEN) for Mb1cre/+ mice; T. Kitami (IMS RIKEN) for the use of the Seahorse Analyser and assistance with Seahorse assays; T. Saito (IMS RIKEN) for the Jurkat cell line; the Iskikawa laboratory (IMS RIKEN) for advice on human tissue staining; M. Li (IMS RIKEN) for help with macrophage cultures; K. Fukuhara (IMS RIKEN) for RNA-seq; and S. Kato for her administrative assistance. This work was supported by the Japan Agency for Medical Research and Development–Core Research for Evolutional Science and Technology (grant 14532135 to S.F.), the Japan Agency for Medical Research and Development-FORCE (grant JP21gm4010008 to S.F.), the RIKEN Aging Project Grant (to S.F.), the Japan Agency for Medical Research and Development–Precursory Research for Innovative Medical Care (JP21gm6110019 to M. Miyajima), the Japan Society for the Promotion of Science KAKENHI Grant-in-Aid for Challenging Research (Exploratory) (grant 21K19392 to M. Miyajima), the Japan Society for the Promotion of Science KAKENHI Grant 18H05411 (K.S.) and the Yanai Fund (Kyoto University); B.Z., A.V., N.H. and T.O. were supported by the RIKEN Special Postdoctoral Researcher (SPDR) Program. The KURAMA cohort study is supported by a grant from Daiichi Sankyo. The funder had no role in the design of the study, the collection or analysis of the data, the writing of the manuscript or the decision to submit the manuscript for publication.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/11/18
Y1 - 2021/11/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85118499045&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85118499045&partnerID=8YFLogxK
U2 - 10.1038/s41586-021-04082-1
DO - 10.1038/s41586-021-04082-1
M3 - Article
C2 - 34732892
AN - SCOPUS:85118499045
SN - 0028-0836
VL - 599
SP - 471
EP - 476
JO - Nature
JF - Nature
IS - 7885
ER -