2. Academic Validation
  3. An epithelial cell-derived metabolite tunes immunoglobulin A secretion by gut-resident plasma cells

An epithelial cell-derived metabolite tunes immunoglobulin A secretion by gut-resident plasma cells

  • Nat Immunol. 2023 Jan 19. doi: 10.1038/s41590-022-01413-w.
Simona Ceglia 1,  Alyssa Berthelette 1,  Kelsey Howley 1,  Yun Li 2,  Benedikt Mortzfeld 3,  Shakti K Bhattarai 3,  Nicole K H Yiew 4,  Ying Xu 5,  Robert Brink 6 7,  Jason G Cyster 5,  Lora V Hooper 2 8,  Gwendalyn J Randolph 4,  Vanni Bucci 3,  Andrea Reboldi 9
Affiliations

Affiliations

  • 1 Department of Pathology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • 2 Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 3 Department of Microbiology and Physiological systems, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • 4 Department of Pathology and Immunology, Washington University Medical School, St. Louis, MO, USA.
  • 5 Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.
  • 6 Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
  • 7 St Vincent's Clinical School, UNSW Sydney, Sydney, New South Wales, Australia.
  • 8 Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 9 Department of Pathology, University of Massachusetts Chan Medical School, Worcester, MA, USA. [email protected].
PMID: 36658240 DOI: 10.1038/s41590-022-01413-w
Abstract

Immunoglobulin A (IgA) secretion by plasma cells, terminally differentiated B cells residing in the intestinal lamina propria, assures microbiome homeostasis and protects the host against enteric infections. Exposure to diet-derived and commensal-derived signals provides immune cells with organizing cues that instruct their effector function and dynamically shape intestinal immune responses at the mucosal barrier. Recent data have described metabolic and microbial inputs controlling T cell and innate lymphoid cell activation in the gut; however, whether IgA-secreting lamina propria plasma cells are tuned by local stimuli is completely unknown. Although antibody secretion is considered to be imprinted during B cell differentiation and therefore largely unaffected by environmental changes, a rapid modulation of IgA levels in response to intestinal fluctuations might be beneficial to the host. In the present study, we showed that dietary Cholesterol absorption and commensal recognition by duodenal intestinal epithelial cells lead to the production of oxysterols, evolutionarily conserved lipids with immunomodulatory functions. Using conditional Cholesterol 25-hydroxylase deleter mouse line we demonstrated that 7α,25-dihydroxycholesterol from epithelial cells is critical to restrain IgA secretion against commensal- and pathogen-derived antigens in the gut. Intestinal plasma cells sense oxysterols via the chemoattractant receptor GPR183 and couple their tissue positioning with IgA secretion. Our findings revealed a new mechanism linking dietary Cholesterol and humoral immune responses centered around plasma cell localization for efficient mucosal protection.

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