45Immunometabolism: mapping pathways and identifying metabolites with immune regulatory functionAntigenic stimulation leads to activation, proliferation and differentiation of immune cells into immediate effector or long-term memory cells able to rees-tablish and maintain homeostasis. The demands for biomass building and syn-thesis of effector molecules require readjustment of cellular metabolism, during which small molecules are likely produced and secreted. We hypothesized that many such molecules derived from metabolic reprogramming induced by im-mune cell activation have functions other than simply serving as intermediates in metabolic pathways. For example, they may function as signaling molecules influencing the immune cells function. We found that antigenic stimulation induced upon immunization significantly elevated the levels of gamma-amino-butyric (GABA) in the activated lymph nodes. This was surprising, as GABA is primarily known as a major neurotransmitter produced by neurons in the cen-tral nervous system. Moreover, the source of GABA in the lymphoid tissues is essentially unknown. Our experiments revealed that B cells are the main source of GABA in lymphoid tissues, raising the possibility that B cell-derived GABA might participate in regulation of immune responses (Figure).Mechanistically we demonstrated that B cell-derived GABA promotes monocyte differentiation into anti-inflammatory macrophages secreting IL-10 and inhibits CD8+ T cell killer function.Understanding the divergent metabolic pathways utilized by different im-mune cell subsets and how the metabolites turn into immunoregulators may, in the future, allow targeted therapeutic approaches that both inhibit tumor cell growth and enhance immunity to cancer, or allow the design of drugs that deli-cately undermine overactive B cell responses in autoimmunity.Figure: Visualization of GABA in lymph nodes after foot pad immunizationImagining mass spectrometry and immunohistochemis-try of ipsilateral or draining inguinal lymph node (upper panels) and contralateral, non-draining inguinal lymph (lower panels) showing GABA overlapping with B cell follicles.Recent Major PublicationsZhang B, Vogelzang A, Miyajima M, Sugiura Y, Wu Y, Chamoto K, Nakano R, Hatae R, Menzies RJ, Sonomura K, Hojo N, Ogawa T, Kobayashi W, Tsutsui Y, Yamamoto S, Maruya M, Narushima S, Suzuki K, Sugiya H, Murakami K, Hashimoto M, Ueno H, Kobayashi T, Ito K, Hirano T, Shi-roguchi K, Matsuda F, Suematsu M, Honjo T, Fagarasan S. B cell-derived GABA elicits IL-10+ macrophages to limit anti-tumour immunity. Nature 599, 471-476 (2021) doi: 10.1038/s41586-021-04082-1Shirakashi M, Maruya M, Hirota K, Tsuruyama T, Matsuo T, Watanabe R, Murata K, Tanaka M, Ito H, Yoshifuji H, Ohmura K, Elewaut D, Sakaguchi S, Fagarasan S, Mimori T, Hashimoto M. Effect of Impaired T Cell Receptor Signaling on the Gut Microbiota in a Mouse Model of Systemic Autoimmunity. Arthritis Rheumatol 74, 641-653 (2021) doi: 10.1002/art.42016Akrami M, Menzies R, Chamoto K, Miyajima M, Suzuki R, Sato H, Nishii A, Tomura M, Fagarasan S, Honjo T. Cir-culation of gut-preactivated naïve CD8+ T cells enhances antitumor immunity in B cell-defective mice. Proc Natl Acad Sci U S A 117, 23674-23683 (2020) doi: 10.1073/pnas.2010981117Invited presentationsFagarasan S. Zhang B (talk) “B cell derived GABA elicits anti-inflammatory macrophages limiting anti-tumor responses” Japanese Society for Immunology Annual Meeting (Nara, Japan) December 2021Fagarasan S. Zhang B (talk) “B cell derived GABA elicits anti-inflammatory macrophages limiting anti-tumor responses” The 19th Awaji International Forum on Infec-tion and Immunity (Online) September 2021Fagarasan S. “The biochemical dialog between major physiological systems mediated by the immune cells” The 25th Annual Meeting of Japanese Association for Cancer Immunology (Online) July 2021Fagarasan S. “The biochemical dialog between major physiological systems mediated by the immune cells” The Uehara International Symposium 2021, Brain-Periphery Interactions in Health and Diseases (Online) June 2021Fagarasan S. “The biochemical dialog between major physiological systems mediated by the immune cells” Kyoto University-University of California San Diego seminars The 9th NIF Winter School on Advanced Im-munology (Online) April 2021Laboratory for Mucosal ImmunityTeam Leader: Sidonia Fagarasan
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