Abstract

The lymphotoxin (LT) beta receptor plays a critical role in secondary lymphoid organogenesis and the classical and alternative NF-kappaB pathways have been implicated in this process. IKKalpha is a key molecule for the activation of the alternative NF-kappaB 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 IKKalpha(AA) 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, IKKalpha(AA) LNs showed reduced lymphoid chemokine CCL19, CCL21, and CXCL13 expression. IKKalpha(AA) 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 LTalphabeta. In this study, analysis of LTbeta(-/-) mice identifies GlyCAM-1 as another LTbeta-dependent gene. In contrast, TNFRI(-/-) mice, which lose classical NF-kappaB pathway activity but retain alternative NF-kappaB pathway activity, showed relatively normal GlyCAM-1 and HEC-6ST expression in LN-HEV. In addition, in this communication, it is demonstrated that LTbetaR is prominently expressed on LN- and NALT-HEV. Thus, these data reveal a critical role for IKKalpha in LN and NALT development, identify GlyCAM-1 and high endothelial cell sulfotransferase as new IKKalpha-dependent target genes, and suggest that LTbetaR signaling on HEV can regulate HEV-specific gene expression.

Highlights

  • We show that IKK␣AA 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 high endothelial venules (HEV)

  • We have studied the contribution of IKK␣, an essential component of the alternative NF-␬B pathway, to LN and NALT organogenesis

  • By using IKK␣AA knockin mice, we provide evidence that IKK␣ activation and kinase activity contribute in a crucial manner to both LN and NALT organogenesis through regulation of tissue cellularity, organization, chemokine expression, and HEV development

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Summary

Abbreviations used in this paper

LT, lymphotoxin; PP, Peyer’s patches; NALT, nasal-associated lymphoid tissue; LN, lymph node; CD62L, L-selectin; BAFF, B cell-activating factor; IKK, I␬B kinase complex; IKK␣AA, IKK␣ kinase inactive; NIK, NF-␬B inducing kinase; MLN, mesenteric lymph node; HEV, high endothelial venule; HEC-6ST, high endothelial cell sulfotransferase; PNAd, peripheral node addressin; GlyCAM-1, glycosylation-dependent cell adhesion molecule 1; DIG, digoxigenin; WT, wild type; FDC, follicular dendritic cell; PLN, peripheral lymph node. Other studies have demonstrated that LT␤R-induced NF-␬B2 processing and RelB nuclear translocation are NIK- and IKK␣-dependent [8, 16] Data implicated both the canonical and alternative NF-␬B pathways in control of lymphoid chemokine expression— CCL19. Given the complete absence of LNs in NIKϪ/Ϫ mice, the relative paucity of LNs in RelBϪ/Ϫ and NF-␬B2Ϫ/Ϫ mice, and IKK␣ perinatal lethality, studies addressing the role of these molecules in secondary lymphoid organogenesis have focused on PP and spleen development and have revealed the absence of PP and multiple splenic defects [24]. We provide in vivo evidence that IKK␣ kinase activity is required for normal LN and NALT organogenesis through regulation of tissue microarchitecture, cellular composition, lymphoid chemokine expression, and HEV-specific gene expression. In addition to highlighting a role for IKK␣ kinase activity in LN and NALT organogenesis, these studies identify GlyCAM-1 and HEC-6ST as new IKK␣-dependent target genes

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