Overlapping Roles of CXCL13, Interleukin 7 Receptor α, and CCR7 Ligands in Lymph Node Development

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Abstract
Lymphoid tissue development is associated with local accumulation of CD4+ CD3− IL-7Rαhi hematopoietic cells that deliver lymphotoxin (LT)α1β2 signals to resident stromal cells. Previous studies have established an important role for CXCL13 (BLC) in the development of Peyer's patches (PP) and some peripheral lymph nodes (LNs), but the chemokine requirements for several LN types, including mesenteric LNs, remain undefined. Using CXCL13−/− mice that additionally carry the paucity of LN T cell mutation (plt/plt), we discovered that CCR7 ligands function in peripheral LN development. We also tested for a genetic interaction during LN development between CXCL13 and a cytokine receptor required in PP development, IL-7Rα. Mice deficient for both CXCL13 and IL-7Rα displayed a striking absence of LNs, including mesenteric LNs. These data extend the role of CXCL13 to the development of all LNs and establish a previously unappreciated role for IL-7Rα in this process. Both circulating and LN CD4+ CD3− IL-7Rαhi cells are shown to express LTα1β2 in an IL-7Rα–dependent manner. Furthermore, CXCL13 was found to be sufficient to mediate CD4+ CD3− IL-7Rαhi cell recruitment in vivo to an ectopic site. These findings indicate that CXCL13 and CCR7 ligands promote accumulation of CD4+ CD3− IL-7Rαhi cells, delivering IL-7Rα–dependent LTα1β2 signals critical for LN development.