Abstract
B cells home to the lymph nodes (LNs) via high endothelial venules (HEVs) under the guidance of chemokines, particularly CXCL13. However, as CXCL13 is not directly made in HEVs, the molecular mechanism mediating B-cell homing to LNs has remained unclear. We show here that nuclear factor (NF)-κB-inducing kinase (NIK), a kinase mediating activation of the noncanonical NF-κB pathway, functions in lymphatic endothelial cells (LECs) to regulate B-cell homing to LNs. LEC-conditional deletion of NIK in mice did not affect the integrity or global function of lymphatic vessels but caused a severe reduction in the frequency of B cells in LNs. The LEC-specific NIK deficiency did not affect the survival of B cells or the frequency of B cells in the spleen. B-cell adoptive transfer studies revealed that the LEC-specific NIK deletion impairs the ability of LNs to recruit B cells. We further show that NIK mediates expression of the chemokines CXCL13 and CCL19 in LECs. Although CCL19 is also expressed in blood endothelial cells (BECs), CXCL13 is not produced in BECs. These results suggest that NIK regulates naive B-cell homing to LNs via mediating production of the B-cell homing chemokine CXCL13 in LECs.
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Acknowledgements
We thank Genentech Inc. for providing the NIK-flox mice. This work was supported by grants from the National Institutes of Health (GM84459, AI057555, AI104519 and AI64639). This study also used the NIH/NCI-supported resources under award number P30CA016672 at The MD Anderson Cancer Center. SZ was supported by a scholarship from the China Scholarship Council (CSC) under the Grant CSC 201506210393. We also thank Professor Wei He for his support.
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JY and SZ designed and performed the experiments, and JY prepared the figures and wrote the manuscript. LZ, XX, HW, ZJ, MG, J-YY and XC contributed to the performance of the experiments. S-CS supervised the work and wrote the manuscript.
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Yang, J., Zhang, S., Zhang, L. et al. Lymphatic endothelial cells regulate B-cell homing to lymph nodes via a NIK-dependent mechanism. Cell Mol Immunol 16, 165–177 (2019). https://doi.org/10.1038/cmi.2017.167
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DOI: https://doi.org/10.1038/cmi.2017.167