Treg engage lymphotoxin beta receptor for afferent lymphatic transendothelial migration
Open accessAbstract
Regulatory T cells (Tregs) are essential to suppress unwanted immunity or inflammation. After islet allo-transplant Tregs must migrate from blood to allograft, then via afferent lymphatics to draining LN to protect allografts. Here we show that Tregs but not non-Treg T cells use lymphotoxin (LT) during migration from allograft to draining LN, and that LT deficiency or blockade prevents normal migration and allograft protection. Treg LTαβ rapidly modulates cytoskeletal and membrane structure of lymphatic endothelial cells; dependent on VCAM-1 and non-canonical NFκB signalling via LTβR. These results demonstrate a form of T-cell migration used only by Treg in tissues that serves an important role in their suppressive function and is a unique therapeutic focus for modulating suppression.
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Binding of Treg lymphotoxin to the lymphotoxin receptor on capillary LECs promotes lamellipodia formation on LECs that contain VCAM and promote transmigration.
“Binding of Treg lymphotoxin to the lymphotoxin receptor expressed on capillary LECs promotes lamellipodia formation on LECs that contain VCAM and promote transmigration (118, 119).”
From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [119]
The Results sections on basal LEC protrusions report that Treg enhance lamellipodia-like structures, that LTβR blockade reduces their growth, and that VCAM-1 is present in protrusions near Treg. The VCAM-1 Results section also reports that blocking VCAM-1 reduces Treg transmigration. The evidence concerns LECs but does not establish that the observed protrusions specifically form on capillary LECs; it also describes them as lamellipodia-like rather than uniformly lamellipodia. (LLM, conf=0.84)
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- Dejardin E.. The lymphotoxin-beta receptor induces different patterns of gene expression via two NF-kappaB pathways. Immunity 17, 525– 535 (2002). 12387745
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- Authors
- Brinkman, C. C., Iwami, D., Hritzo, M. K., Xiong, Y., Ahmad, S., Simon, T., Hippen, K. L., Blazar, B. R., & Bromberg, J. S.
- Affiliations
- University of Maryland, Baltimore (US)
- University of Minnesota (US)
- Corresponding author
- Bromberg, Jonathan S.
- ORCID
- Venue
- Nature Communications
- Published
- 2016-06-21
- Volume
- 7
- Issue
- 1
- Pages
- 12021-12021
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4919545
- OpenAlex
- W2461482933
- Cited by
- 76
- References
- 55
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 8 · 2023: 7 · 2022: 8 · 2021: 14 · 2020: 7 · 2019: 4 · 2018: 6 · 2017: 8 · 2016: 2
- FWCI
- 4.04
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Hokkaido University Collection of Scholarly and Academic Papers (Hokkaido University) (submittedVersion, cc-by)
- Funders
- Biogen
- American Society of Transplant Surgeons
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland
- National Heart, Lung, and Blood Institute (R01HL056067, R01HL118979)
- National Cancer Institute (P01CA142106, R01CA072669, T32CA154274, P01CA065493)
- National Institute of Allergy and Infectious Diseases (R01AI034495, R01AI062765, P01AI056299, R37AI062765)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Keywords
- regulatory T cells, lymphotoxin beta receptor, transendothelial migration, lymphatic endothelial cells, VCAM-1, islet allografts, immunosuppression
- MeSH terms
- Animals, Diabetes Mellitus, Experimental, Gene Expression Regulation, Graft Rejection, Graft Survival, Islets of Langerhans, Lymph Nodes, Mice, Inbred BALB C, Mice, Inbred C57BL, Transplantation, Homologous, Signal Transduction, Survival Analysis, NF-kappa B, Islets of Langerhans Transplantation, Mice, Knockout, Vascular Cell Adhesion Molecule-1, Lymphatic Vessels, Endothelial Cells, T-Lymphocytes, Regulatory, Mice, Lymphotoxin beta Receptor, Lymphotoxin alpha1, beta2 Heterotrimer, Transendothelial and Transepithelial Migration
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