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Nature
Nov, 2024;635 (8039): 736-745.

A lymphocyte chemoaffinity axis for lung, non-intestinal mucosae and CNS.

Borja Ocón, Menglan Xiang, Yuhan Bi, Serena Tan, Kevin Brulois, Aiman Ayesha, Manali Kunte, Catherine Zhou, Melissa LaJevic, Nicole Lazarus, Francesca Mengoni, Tanya Sharma, Stephen Montgomery, Jody E Hooper, Mian Huang, Tracy Handel, John R D Dawson, Irina Kufareva, Brian A Zabel, Junliang Pan, Eugene C Butcher
Author Information
  1. Borja Ocón: Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. boconmor@stanford.edu. ORCID
  2. Menglan Xiang: Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. mxiang1@stanford.edu. ORCID
  3. Yuhan Bi: Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. yub10@stanford.edu. ORCID
  4. Serena Tan: Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
  5. Kevin Brulois: Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
  6. Aiman Ayesha: Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. ORCID
  7. Manali Kunte: Palo Alto Veterans Institute for Research, Palo Alto, CA, USA.
  8. Catherine Zhou: Palo Alto Veterans Institute for Research, Palo Alto, CA, USA.
  9. Melissa LaJevic: Palo Alto Veterans Institute for Research, Palo Alto, CA, USA.
  10. Nicole Lazarus: Palo Alto Veterans Institute for Research, Palo Alto, CA, USA.
  11. Francesca Mengoni: Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
  12. Tanya Sharma: Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
  13. Stephen Montgomery: Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. ORCID
  14. Jody E Hooper: Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. ORCID
  15. Mian Huang: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA.
  16. Tracy Handel: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA.
  17. John R D Dawson: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA.
  18. Irina Kufareva: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA.
  19. Brian A Zabel: Palo Alto Veterans Institute for Research, Palo Alto, CA, USA.
  20. Junliang Pan: Palo Alto Veterans Institute for Research, Palo Alto, CA, USA. ORCID
  21. Eugene C Butcher: Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. ORCID
PMID: 39293486 DOI: 10.1038/s41586-024-08043-2

Abstract

Tissue-selective chemoattractants direct lymphocytes to epithelial surfaces to establish local immune environments, regulate immune responses to food antigens and commensal organisms, and protect from pathogens. Homeostatic chemoattractants for small intestines, colon and skin are known, but chemotropic mechanisms selective for respiratory tract and other non-intestinal mucosal tissues remain poorly understood. Here we leveraged diverse omics datasets to identify GPR25 as a lymphocyte receptor for CXCL17, a chemoattractant cytokine whose expression by epithelial cells of airways, upper gastrointestinal and squamous mucosae unifies the non-intestinal mucosal tissues and distinguishes them from intestinal mucosae. Single-cell transcriptomic analyses show that GPR25 is induced on innate lymphocytes before emigration to the periphery, and is imprinted in secondary lymphoid tissues on activated B and T cells responding to immune challenge. GPR25 characterizes B and T tissue resident memory cells and regulatory T lymphocytes in non-intestinal mucosal tissues and lungs in humans and mediates lymphocyte homing to barrier epithelia of the airways, oral cavity, stomach, and biliary and genitourinary tracts in mouse models. GPR25 is also expressed by T cells in cerebrospinal fluid and CXCL17 by neurons, suggesting a role in central nervous system (CNS) immune regulation. We reveal widespread imprinting of GPR25 on regulatory T cells, suggesting a mechanistic link to population genetics evidence that GPR25 is protective in autoimmunity. Our results define a GPR25-CXCL17 chemoaffinity axis with the potential to integrate immunity and tolerance at non-intestinal mucosae and the CNS.

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Grants

  1. R21 AI149369/NIAID NIH HHS
  2. I01 BX004115/BLRD VA
  3. R21 AI156662/NIAID NIH HHS
  4. R01 MH125244/NIMH NIH HHS
  5. R01 AI047822/NIAID NIH HHS
  6. R01 GM136202/NIGMS NIH HHS
  7. R01 AI161880/NIAID NIH HHS

MeSH Term

Animals
Female
Humans
Male
Mice
B-Lymphocytes
Central Nervous System
Chemokines, CXC
Chemotaxis
Immunity, Innate
Lung
Lymphocytes
Mice, Inbred C57BL
Mucous Membrane
Receptors, G-Protein-Coupled
T-Lymphocytes, Regulatory
Organ Specificity
Single-Cell Gene Expression Analysis
Immunologic Memory
Epithelial Cells
Neurons
Autoimmune Diseases
Immune Tolerance

Chemicals

Chemokines, CXC
Receptors, G-Protein-Coupled
GPR25 protein, human
CXCL17 protein, human
Journal Article
Article has an altmetric score of 10

Word Cloud

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