Regulation of T cell afferent lymphatic migration by targeting LTβR-mediated non-classical NFκB signaling

Wenji Piao, Yanbao Xiong, Konrad Famulski, C. Colin Brinkman, Lushen Li, Nicholas Toney, Chelsea Wagner, Vikas Saxena, Thomas Simon and Jonathan S. Bromberg ()
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Wenji Piao: University of Maryland School of Medicine
Yanbao Xiong: University of Maryland School of Medicine
Konrad Famulski: University of Alberta
C. Colin Brinkman: University of Maryland School of Medicine
Lushen Li: University of Maryland School of Medicine
Nicholas Toney: University of Maryland School of Medicine
Chelsea Wagner: University of Maryland School of Medicine
Vikas Saxena: University of Maryland School of Medicine
Thomas Simon: University of Maryland School of Medicine
Jonathan S. Bromberg: University of Maryland School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract Lymphotoxin-beta receptor (LTβR) signaling in lymphatic endothelial cells (LEC) regulates leukocyte afferent lymphatic transendothelial migration (TEM). The function of individual signaling pathways for different leukocyte subsets is currently unknown. Here, we show that LTβR signals predominantly via the constitutive and ligand-driven non-classical NIK pathway. Targeting LTβR-NIK by an LTβR-derived decoy peptide (nciLT) suppresses the production of chemokines CCL21 and CXCL12, and enhances the expression of classical NFκB-driven VCAM-1 and integrin β4 to retain T cells on LEC and precludes T cell and dendritic cell TEM. nciLT inhibits contact hypersensitivity (CHS) at both the sensitization and elicitation stages, likely by inhibiting leukocyte migration. By contrast, targeting LTβR-classical NFκB signaling during the elicitation and resolution stages attenuates CHS, possibly by promoting leukocyte egress. These findings demonstrate the importance of LTβR signaling in leukocyte migration and LEC and lymphatic vessel function, and show that antagonist peptides may serve as lead compounds for therapeutic applications.

Date: 2018
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DOI: 10.1038/s41467-018-05412-0

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