B cell-derived GABA elicits IL-10+ macrophages to limit anti-tumour immunity
（Nature， IF： 40。639）
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 & Sidonia Fagarasanx
CORRESPONDENCE TO： Sidonia。fagarasan@riken。jp
Small， soluble metabolites not only are essential intermediates in intracellular biochemical processes but can also influence neighbouring cells when released into the extracellular milieu。 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。
小的可溶性代謝物不僅是細胞內生化過程中必不可少的中間產物，而且在釋放到細胞外環境中時也會影響鄰近細胞。此處我們確定代謝物和神經遞質GABA是由活化的B細胞和漿細胞合成和分泌的候選訊號分子。我們發現，B細胞衍生的GABA促進單核細胞分化為分泌白細胞介素-10並抑制CD8+T細胞殺傷功能的抗炎巨噬細胞。在小鼠中，GABA生成酶GAD67的B細胞缺陷或B細胞特異性失活可增強抗腫瘤反應。我們的研究表明，除了細胞因子和膜蛋白外，來自B系細胞的小代謝物還具有免疫調節功能，此功能或許可微調免疫反應的藥物靶點。
