Lymphotoxin-β Receptor Signaling Is Required for the Homeostatic Control of HEV Differentiation and Function

Abstract

The lymphotoxin axis is important for the maintenance of several specialized lymphoid microenvironments in secondary lymphoid tissue. Lymphoid-tissue architecture is highly plastic and requires continual homeostatic signaling to maintain its basal functional state. The cellularity of lymph nodes in adult mice was reduced by systemic blockade of lymphotoxin-beta receptor (LTbeta R) signaling with a soluble decoy receptor both in resting and reactive settings. This reduction in cellularity resulted from greatly impaired lymphocyte entry into lymph nodes due to decreased levels of peripheral lymph node addressing (PNAd) and MAdCAM on high endothelial venules (HEV). LTbeta R signaling was required to maintain normal levels of RNA expression of MAdCAM, and also of PNAd by regulating the expression of key enzymes and scaffold proteins required for its assembly. Thus, the homeostatic maintenance of functional HEV status in adult mice relies largely on LTbeta R signaling.

Absence of Nkx2-3 Homeodomain Transcription Factor Reprograms the Endothelial Addressin Preference for Lymphocyte Homing in Peyer’s Patches

“…Appearance of mature PNAd + HEVs could efficiently be blocked by administration of soluble LTbR decoy receptor. This is in line with previous reports showing the importance of LTbR signaling in HEV differentiation and function in wild-type mice (30). Possible sources of the non-T/non-B LT signals in the Nkx2-3 2/2 3 Rag1 2/2 double mutants are CD11c + dendritic cells that have been shown to influence HEV development and maintenance (32) and also retinoic acid-related orphan receptor gt + innate lymphoid cells, which have been reported to express LT (33).…”

“…In this process members of the TNF/LT induce the expression of stromal and endothelial MAdCAM-1, which is required for the initial recruitment of lymphocytes to the forming PP anlage (29,30). In Nkx2-3 2/2 mice MAdCAM-1 expression is preserved in PPs until the perinatal period, in agreement with previous data demonstrating HEV-associated MAdCAM-1 in neonatal mLNs (17).…”

“…This process coincides with the colonization of developing LNs with T and B lymphocytes, and it requires signaling through LTbR expressed on endothelial cells (30,31). Given the pLN-like shift of lymphocyte composition and endothelial addressin expression in Nkx2-3 mutant PPs, we next investigated the lymphoid cellular and LT requirements of this process.…”

B Lymphocyte Autoimmunity in Rheumatoid Synovitis Is Independent of Ectopic Lymphoid Neogenesis

“…A second factor of interest is the low expression of LTb, even in the presence of lymphoid neogenesis. LTb controls HEV development and function in SLO (24,53) and predicts FDC recruitment in inflamed synovium (15). The low LTb expression is consistent with our observation that these tissues do no contain HEVs and FDCs.…”

The unexpected role of lymphotoxin β receptor signaling in carcinogenesis: from lymphoid tissue formation to liver and prostate cancer development

“…Inflamed sites in RIPLTa or RIPLTab mice are vascularized with endothelia showing morphologic characteristics of high endothelial venules (Picarella et al, 1992;Cuff et al, 1999;Drayton et al, 2003). Further, it has been reported that LTbR signaling is a requirement for the homeostatic control of high endothelial venule differentiation and function (Browning et al, 2005). Overexpression of LTab under the liver-specific albumin promoter (AlbLTab) led to chronic hepatitis, organized portal and lobular lymphocytic infiltrates, follicular dendritic cells and germinal centers leading to mild, chronic liver damage ( This leads to the activation of the IKK complex by phosphorylation of NEMO/IKKg and IKKb, which results in the phosphorylation of IkBa, its subsequent ubiquitylation and proteasomal degradation.…”