Inflammation switches the chemoattractant requirements for naive lymphocyte entry into lymph nodes

Kevin Y Chen; Marco De Giovanni; Ying Xu; Jinping An; Nikhita Kirthivasan; Erick Lu; Kan Jiang; Stephen Brooks; Serena Ranucci; Jiuling Yang; Shuto Kanameishi; Kenji Kabashima; Kevin Brulois; Michael Bscheider; Eugene C Butcher; Jason G Cyster

doi:10.1016/j.cell.2024.11.031

Inflammation switches the chemoattractant requirements for naive lymphocyte entry into lymph nodes

Cell. 2024 Dec 17:S0092-8674(24)01347-3. doi: 10.1016/j.cell.2024.11.031. Online ahead of print.

Authors

Affiliations

¹ Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Medical Scientist Training Program, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: kevin.chen3@ucsf.edu.
² Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
³ Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA.
⁴ Biodata Mining and Discovery Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
⁵ Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
⁶ Department of Urology, University of California, San Francisco, San Francisco, CA 94143, USA.
⁷ Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
⁸ Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Palo Alto Veterans Institute for Research, Palo Alto, CA, USA.
⁹ Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: jason.cyster@ucsf.edu.

PMID: 39708807
DOI: 10.1016/j.cell.2024.11.031

Abstract

Sustained lymphocyte migration from blood into lymph nodes (LNs) is important for immune responses. The CC-chemokine receptor-7 (CCR7) ligand CCL21 is required for LN entry but is downregulated during inflammation, and it has been unclear how recruitment is maintained. Here, we show that the oxysterol biosynthetic enzyme cholesterol-25-hydroxylase (Ch25h) is upregulated in LN high endothelial venules during viral infection. Lymphocytes become dependent on oxysterols, generated through a transcellular endothelial-fibroblast metabolic pathway, and the receptor EBI2 for inflamed LN entry. Additionally, Langerhans cells are an oxysterol source. Ch25h is also expressed in inflamed peripheral endothelium, and EBI2 mediates B cell recruitment in a tumor model. Finally, we demonstrate that LN CCL19 is critical in lymphocyte recruitment during inflammation. Thus, our work explains how naive precursor trafficking is sustained in responding LNs, identifies a role for oxysterols in cell recruitment into inflamed tissues, and establishes a logic for the CCR7 two-ligand system.

Keywords: CCL19; CCL21; GPR183; cholesterol metabolites; high endothelial venules; lymph nodes; lymphocyte trafficking; stromal cells; tumors; viral infection.