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.
Highlights
Lymphotoxin-beta receptor (LTβR) signaling in lymphatic endothelial cells (LEC) regulates leukocyte afferent lymphatic transendothelial migration (TEM)
T cell migration are distinct from those used by DC, neutrophil, or monocyte migration, in that T cell migration is governed by integrin-independent mechanisms, such as S1P/S1PR1-mediated homeostatic T cell trafficking[2] and LTα1β2/lymphotoxin-beta receptor (LTβR)-mediated regulatory T cells (Treg) entry into lymphatics[3]
LTβ receptor (LTβR) activation resulted in classical NFκB signaling, rapid RelA nuclear translocation, and VCAM-1 and CCL2 expression associated with cell migration during inflammation
Summary
Lymphotoxin-beta receptor (LTβR) signaling in lymphatic endothelial cells (LEC) regulates leukocyte afferent lymphatic transendothelial migration (TEM). 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. A unique mechanism employed by Treg is the high level expression of cell surface lymphotoxin (LT), which is required for migration from the allograft to afferent lymphatics and to the draining LN3 This LT-dependent mechanism is neither required to enter LN via the HEV, nor for egress from the LN to efferent lymphatics.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
