Mast cells link immune sensing to antigen-avoidance behaviour

Thomas Plum (), Rebecca Binzberger, Robin Thiele, Fuwei Shang, Daniel Postrach, Candice Fung, Marina Fortea, Nathalie Stakenborg, Zheng Wang, Anke Tappe-Theodor, Tanja Poth, Duncan A. A. MacLaren, Guy Boeckxstaens, Rohini Kuner, Claudia Pitzer, Hannah Monyer, Cuiyan Xin, Joseph V. Bonventre, Satoshi Tanaka, David Voehringer, Pieter Vanden Berghe, Jessica Strid, Thorsten B. Feyerabend and Hans-Reimer Rodewald ()
Additional contact information
Thomas Plum: German Cancer Research Center
Rebecca Binzberger: German Cancer Research Center
Robin Thiele: German Cancer Research Center
Fuwei Shang: German Cancer Research Center
Daniel Postrach: German Cancer Research Center
Candice Fung: KU Leuven
Marina Fortea: KU Leuven
Nathalie Stakenborg: KU Leuven
Zheng Wang: KU Leuven
Anke Tappe-Theodor: Heidelberg University
Tanja Poth: Heidelberg University Hospital
Duncan A. A. MacLaren: Department of Clinical Neurobiology of the Medical Faculty of Heidelberg University and German Cancer Research Center
Guy Boeckxstaens: KU Leuven
Rohini Kuner: Heidelberg University
Claudia Pitzer: Heidelberg University
Hannah Monyer: Department of Clinical Neurobiology of the Medical Faculty of Heidelberg University and German Cancer Research Center
Cuiyan Xin: Brigham and Women’s Hospital, Harvard Medical School
Joseph V. Bonventre: Brigham and Women’s Hospital, Harvard Medical School
Satoshi Tanaka: Kyoto Pharmaceutical University
David Voehringer: University Hospital Erlangen and Friedrich-Alexander University Erlangen-Nuremberg
Pieter Vanden Berghe: KU Leuven
Jessica Strid: Imperial College London
Thorsten B. Feyerabend: German Cancer Research Center
Hans-Reimer Rodewald: German Cancer Research Center

Nature, 2023, vol. 620, issue 7974, 634-642

Abstract: Abstract The physiological functions of mast cells remain largely an enigma. In the context of barrier damage, mast cells are integrated in type 2 immunity and, together with immunoglobulin E (IgE), promote allergic diseases. Allergic symptoms may, however, facilitate expulsion of allergens, toxins and parasites and trigger future antigen avoidance1–3. Here, we show that antigen-specific avoidance behaviour in inbred mice4,5 is critically dependent on mast cells; hence, we identify the immunological sensor cell linking antigen recognition to avoidance behaviour. Avoidance prevented antigen-driven adaptive, innate and mucosal immune activation and inflammation in the stomach and small intestine. Avoidance was IgE dependent, promoted by Th2 cytokines in the immunization phase and by IgE in the execution phase. Mucosal mast cells lining the stomach and small intestine rapidly sensed antigen ingestion. We interrogated potential signalling routes between mast cells and the brain using mutant mice, pharmacological inhibition, neural activity recordings and vagotomy. Inhibition of leukotriene synthesis impaired avoidance, but overall no single pathway interruption completely abrogated avoidance, indicating complex regulation. Collectively, the stage for antigen avoidance is set when adaptive immunity equips mast cells with IgE as a telltale of past immune responses. On subsequent antigen ingestion, mast cells signal termination of antigen intake. Prevention of immunopathology-causing, continuous and futile responses against per se innocuous antigens or of repeated ingestion of toxins through mast-cell-mediated antigen-avoidance behaviour may be an important arm of immunity.

Date: 2023
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DOI: 10.1038/s41586-023-06188-0

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