Lymph node (LN) function depends on T and B cell compartmentalization, antigen presenting cells, and high endothelial venules (HEVs) expressing mucosal addressin cell adhesion molecule (MAdCAM-1) and peripheral node addressin (PNAd), ligands for naive cell entrance into LNs. Luminal PNAd expression requires a HEV-restricted sulfotransferase (HEC-6ST). To investigate LTαβ's activities in lymphoid organogenesis, mice simultaneously expressing LTα and LTβ under rat insulin promoter II (RIP) control were compared with RIPLTα mice in a model of lymphoid neogenesis and with LTβ−/− mice. RIPLTαβ pancreata exhibited massive intra-islet mononuclear infiltrates that differed from the more sparse peri-islet cell accumulations in RIPLTα pancreata: separation into T and B cell areas was more distinct with prominent FDC networks, expression of lymphoid chemokines (CCL21, CCL19, and CXCL13) was more intense, and L-selectin+ cells were more frequent. In contrast to the predominant abluminal PNAd pattern of HEV in LTβ−/− MLN and RIPLTα pancreatic infiltrates, PNAd was expressed at the luminal and abluminal aspects of HEV in wild-type LN and in RIPLTαβ pancreata, coincident with HEC-6ST. These data highlight distinct roles of LTα and LTαβ in lymphoid organogenesis supporting the notion that HEC-6ST–dependent luminal PNAd is under regulation by LTαβ.

The lymphotoxin (LT) β receptor plays a critical role in secondary lymphoid organogenesis and the classical and alternative NF-κB pathways have been implicated in this process. IKKα is a key molecule for the activation of the alternative NF-κB pathway. However, its precise role and target genes in secondary lymphoid organogenesis remain unknown, particularly with regard to high endothelial venules (HEV). In this study, we show that IKKαAA mutant mice, who lack inducible kinase activity, have hypocellular lymph nodes (LN) and nasal-associated lymphoid (NALT) tissue characterized by marked defects in microarchitecture and HEV. In addition, IKKαAA LNs showed reduced lymphoid chemokine CCL19, CCL21, and CXCL13 expression. IKKαAA LN- and NALT-HEV were abnormal in appearance with reduced expression of peripheral node addressin (PNAd) explained by a severe reduction in the HEV-associated proteins, glycosylation-dependent cell adhesion molecule 1 (GlyCAM-1), and high endothelial cell sulfotransferase, a PNAd-generating enzyme that is a target of LTαβ. In this study, analysis of LTβ−/− mice identifies GlyCAM-1 as another LTβ-dependent gene. In contrast, TNFRI−/− mice, which lose classical NF-κB pathway activity but retain alternative NF-κB pathway activity, showed relatively normal GlyCAM-1 and HEC-6ST expression in LN-HEV. In addition, in this communication, it is demonstrated that LTβR is prominently expressed on LN- and NALT-HEV. Thus, these data reveal a critical role for IKKα in LN and NALT development, identify GlyCAM-1 and high endothelial cell sulfotransferase as new IKKα-dependent target genes, and suggest that LTβR signaling on HEV can regulate HEV-specific gene expression.

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