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 and Eugene C. Butcher
Additional contact information
Borja Ocón: Stanford University School of Medicine
Menglan Xiang: Stanford University School of Medicine
Yuhan Bi: Stanford University School of Medicine
Serena Tan: Stanford University School of Medicine
Kevin Brulois: Stanford University School of Medicine
Aiman Ayesha: Stanford University School of Medicine
Manali Kunte: Palo Alto Veterans Institute for Research
Catherine Zhou: Palo Alto Veterans Institute for Research
Melissa LaJevic: Palo Alto Veterans Institute for Research
Nicole Lazarus: Palo Alto Veterans Institute for Research
Francesca Mengoni: Stanford University School of Medicine
Tanya Sharma: Stanford University School of Medicine
Stephen Montgomery: Stanford University School of Medicine
Jody E. Hooper: Stanford University School of Medicine
Mian Huang: University of California San Diego
Tracy Handel: University of California San Diego
John R. D. Dawson: University of California San Diego
Irina Kufareva: University of California San Diego
Brian A. Zabel: Palo Alto Veterans Institute for Research
Junliang Pan: Palo Alto Veterans Institute for Research
Eugene C. Butcher: Stanford University School of Medicine

Nature, 2024, vol. 635, issue 8039, 736-745

Abstract: 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 known1,2, 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 autoimmunity3,4. Our results define a GPR25–CXCL17 chemoaffinity axis with the potential to integrate immunity and tolerance at non-intestinal mucosae and the CNS.

Date: 2024
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DOI: 10.1038/s41586-024-08043-2

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