BCAD42Immunometabolism: mapping pathways and identifying metabolites with immune regulatory functionThe evolving field of immunoregulation studies how the activity of lympho-cytes is shaped by their local environment via a variety of receptor interactions with soluble and cell-bound proteins. However, small metabolites derived from immune cell metabolism are likely present in both intracellular and extracel-lular milieu in vivo, many of which may have signaling potential that we have yet to understand. We hypothesized that water-soluble metabolites provide environmental cues mediating interactions between immune cells to impact on their function. We generated contrasting samples representing immune cell homeostasis and activation using a classic footpad immunization with ovalbu-min (OVA) protein emulsified in complete Freund’s adjuvant (CFA). We then performed comprehensive metabolome profiling of the ipsilateral (activated, or draining) and contralateral (resting, or non-draining) popliteal lymph nodes (LNs) in WT and immunodeficient animals lacking T cells (cd3e-/-), B cells (muMt-/-) or all mature T and B cells (rag1-/-). We identified the metabolite and neurotransmitter GABA (4-Aminobutyric acid) as a candidate signaling mol-ecule synthesized in a B cell-dependent manner (Figure) and confirmed that GABA is produced and secreted predominantly by activated B cells and plasma cells. We recently found that B cell deficient mice (uMT mice) have enhanced anti-tumor responses (Akrami et al., PNAS, 2020). We tested whether B cell-derived GABA may be limiting cytotoxic T cell activity and indeed found en-hanced anti-tumor responses in mice with B cell-specific inactivation of the GABA generating enzyme GAD67. Mechanistically we demonstrate that B cell-derived GABA promotes monocyte differentiation into anti-inflammatory mac-rophages secreting IL-10 and inhibiting CD8+ T cell killer function. Unraveling the differing metabolic requirements of specific immune subsets has particular relevance in cancer, as a growing number of therapies in development target the metabolic enzymes active in highly-proliferative tumor cells. Understanding the divergent metabolic pathways utilized in B cells, T cells and macrophages 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 delicately undermine overactive B cell responses in autoimmunity.Figure: Metabolic remodeling and B cell-depen-dent GABA (4-Aminobutyric acid) production in draining lymph nodes upon immunizationA. Footpad immunization scheme; B. Principal compo-nent analyses of metabolites extracted from contralater-al LN and ipsilateral LN C. Volcano plot and D. Heatmap showing metabolites that differed significantly between contralateral LN and ipsilateral LN.Recent Major PublicationsAkrami 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)Guzman-Bautista ER, Suzuki K, Asami S, Fagarasan S. Bacteria-immune cells dialog and the homeostasis of the systems. Curr Opin Immunol 66, 82-89 (2020)Hatae R, Chamoto K, Kim YH, Sonomura K, Taneishi K, Kawaguchi S, Yoshida H, Ozasa H, Sakamori Y, Akrami M, Fagarasan S, Masuda I, Okuno Y, Matsuda F, Hirai T, Honjo H. Combination of host immune metabolic bio-markers for the PD-1 blockade cancer immunotherapy. JCI Insight, 5 (2020)Invited presentationsFagarasan S. “Shaping of microbial landscape and sys-temic biochemistry by adaptive immune system” The 9th NIF Winter School on Advanced Immunology (Awaji, Japan) January 2020Fagarasan S. “The biochemical dialog between major physiological systems mediated by immune cells” MBSJ 2020 (Online) December 2020Laboratory for Mucosal ImmunityTeam Leader: Sidonia Fagarasan
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