Lymphotoxin Signaling in Lymphoid Organogenesis
Summary
Lymphoid organogenesis is orchestrated by the coordinated interaction between lymphoid tissue inducer cells and mesenchymal organiser cells under the control of lymphotoxin signalling. Lymphotoxin-α (LTα), secreted as a homotrimer, and lymphotoxin-α1β2 (LTα1β2), presented as a membrane-anchored heterotrimer, engage the lymphotoxin-β receptor (LTβR) on stromal organiser cells. This engagement triggers NF-κB and alternative non-canonical pathways to induce chemokines such as CCL19, CCL21 and CXCL13. These chemokines recruit and compartmentalise developing B and T lymphocytes, guiding the formation of lymph nodes, Peyer’s patches and splenic white pulp. Concurrently, lymphotoxin signalling drives the differentiation of fibroblastic reticular cells and the maturation of high endothelial venules, ensuring proper lymphocyte trafficking. Genetic ablation of lymphotoxin subunits or LTβR results in agenesis or disorganisation of secondary lymphoid tissues, demonstrating the non-redundant role of this axis. Beyond development, lymphotoxin signals regulate tissue regeneration after injury and maintain tertiary lymphoid structures in chronic inflammation, highlighting its broader significance. Understanding the precise timing, cellular sources and downstream effectors of lymphotoxin signalling has profound implications for vaccine design, immunotherapeutics and the treatment of autoimmune pathologies characterised by ectopic lymphoid neogenesis.
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Lymphotoxin Signaling in Lymphoid Organogenesis publication trend
The graph below shows the total number of articles in lymphotoxin signaling in lymphoid organogenesis across all publications each year (not limited to Nature Index journals).
Technical terms
Lymphoid tissue inducer (LTi) cell: A haematopoietic population that initiates organogenesis by expressing lymphotoxin and interacting with stromal organiser cells.
Fibroblastic reticular cell (FRC): A specialised stromal cell in lymphoid organs that forms a reticular network and secretes chemokines guiding lymphocyte localisation.
LTβ receptor (LTβR): A member of the tumour necrosis factor receptor family that binds LTα1β2 heterotrimers to activate NF-κB signalling and organ-building programmes.
Innate lymphoid cell type 3 (ILC3): A group of innate immune cells that produce TNF family cytokines and contribute to the maturation of secondary lymphoid structures.
Chemokine gradients: Spatial distributions of small cytokines such as CCL19, CCL21 and CXCL13 that direct the migration and segregation of lymphocyte subsets during organogenesis.
References
- LTα, TNF, and ILC3 in Peyer’s Patch Organogenesis. Cells (2022).
- T lymphocytes maintain structure and function of fibroblastic reticular cells via lymphotoxin (LT)-B. BMC Immunology (2014).
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