Inflammation switches the chemoattractant requirements for naive lymphocyte entry into lymph nodes
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.
Authors
- Kevin Y. Chen (ORCID: https://orcid.org/0000-0001-5299-8368)
- Shuto Kanameishi (ORCID: https://orcid.org/0000-0002-1616-1349)
- Kenji Kabashima (ORCID: https://orcid.org/0000-0002-0773-0554)
- Eugene C. Butcher
- Jinping An (ORCID: https://orcid.org/0009-0009-5158-4505)
- Serena Ranucci (ORCID: https://orcid.org/0000-0001-7177-2188)
- Marco De Giovanni (ORCID: https://orcid.org/0000-0001-7521-3092)
- Jason G. Cyster (ORCID: https://orcid.org/0000-0002-4735-9745)
- Kevin Brulois (ORCID: https://orcid.org/0000-0002-6024-6075)
- Erick Lu (ORCID: https://orcid.org/0000-0001-8175-5146)
- Kan Jiang (ORCID: https://orcid.org/0009-0002-1402-0355)
- Michael Bscheider (ORCID: https://orcid.org/0000-0001-7808-3270)
- Ying Xu (ORCID: https://orcid.org/0000-0001-9994-9889)
- Stephen R. Brooks (ORCID: https://orcid.org/0000-0001-5592-5332)
- Jiuling Yang (ORCID: https://orcid.org/0000-0002-5301-6976)
- Nikhita Kirthivasan (ORCID: https://orcid.org/0009-0005-4864-7799)
Institutions
- National Institutes of Health (US)
- Howard Hughes Medical Institute (US)
- University of California, San Francisco (US)
- Kyoto University (JP)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (US)
- Palo Alto Veterans Institute for Research (US)
- University of California San Francisco Medical Center (US)
Publication Details
- Journal
- Cell
- Published
- 2024-12-20
- DOI
- https://doi.org/10.1016/j.cell.2024.11.031
- Citations
- 34
- Primary Topic
- Immunotherapy and Immune Responses
- Type
- article
- Field-Weighted Citation Impact
- 8.18
Funders
- U.S. Department of Veterans Affairs
- Emory University
- Leona M. and Harry B. Helmsley Charitable Trust
- National Institutes of Health
- University of California, San Francisco
- National Institute of General Medical Sciences
- National Institute of Allergy and Infectious Diseases