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Intracellular sterol sensing controls intestinal B cell differentiation

Bruno C. Trindade, Simona Ceglia, Alyssa Berthelette, Fiona Raso, Kelsey Howley, View ORCID ProfileJagan R. Muppidi, View ORCID ProfileAndrea Reboldi
doi: https://doi.org/10.1101/2020.11.03.367177
Bruno C. Trindade
1Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA
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Simona Ceglia
1Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA
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Alyssa Berthelette
1Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA
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Fiona Raso
1Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA
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Kelsey Howley
1Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA
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Jagan R. Muppidi
2Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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Andrea Reboldi
1Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA
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  • ORCID record for Andrea Reboldi
  • For correspondence: andrea.reboldi@umassmed.edu
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Abstract

Intestinal B cell responses are critical for the maintenance of gut homeostasis, yet environmental signals that control B cell metabolism and effector function remain poorly characterized. Here, we show that Peyer’s patches germinal center (GC) B cells are sensitive to 25-hydroxycholesterol (25-HC), an oxidized metabolite of cholesterol produced by the enzyme cholesterol 25-hydroxylase (CH25H). In mice lacking CH25H, antigen-specific GC B cells show an increased cholesterol metabolic signature and preferentially differentiate in plasma cells (PCs), thereby inducing a stronger intestinal IgA response upon immunization or infection. GC B cells express the sterol sensor SREBP2 and use it to sense 25-HC. Deletion of SREBP2 from GC B cells prevents PC differentiation and forces the maintenance of GC identity. GC localized oxysterol production by follicular dendritic cells is central in dictating GC metabolism and imposing B cell fate. Our findings show that the 25-HC-SREBP2 axis shapes B cell effector function in intestinal lymphoid organs and indicate that dietary cholesterol can instruct local B cell response.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted March 11, 2021.
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Intracellular sterol sensing controls intestinal B cell differentiation
Bruno C. Trindade, Simona Ceglia, Alyssa Berthelette, Fiona Raso, Kelsey Howley, Jagan R. Muppidi, Andrea Reboldi
bioRxiv 2020.11.03.367177; doi: https://doi.org/10.1101/2020.11.03.367177
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Intracellular sterol sensing controls intestinal B cell differentiation
Bruno C. Trindade, Simona Ceglia, Alyssa Berthelette, Fiona Raso, Kelsey Howley, Jagan R. Muppidi, Andrea Reboldi
bioRxiv 2020.11.03.367177; doi: https://doi.org/10.1101/2020.11.03.367177

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