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

Howard Hughes Medical Institute (HHMI) and Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143

Address correspondence to Jason G. Cyster, Department of Microbiology and Immunology, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143. Phone: 415-502-6427; Fax: 415-502-8424; E-mail: cyster{at}itsa.ucsf.edu

Lymphoid tissue development is associated with local accumulation of CD4⁺ CD3^- IL-7R^hi hematopoietic cells that deliver lymphotoxin (LT)1ß2 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-7R. Mice deficient for both CXCL13 and IL-7R 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-7R in this process. Both circulating and LN CD4⁺ CD3^- IL-7R^hi cells are shown to express LT1ß2 in an IL-7R–dependent manner. Furthermore, CXCL13 was found to be sufficient to mediate CD4⁺ CD3^- IL-7R^hi cell recruitment in vivo to an ectopic site. These findings indicate that CXCL13 and CCR7 ligands promote accumulation of CD4⁺ CD3^- IL-7R^hi cells, delivering IL-7R–dependent LT1ß2 signals critical for LN development.

Key Words: organogenesis • CXCR5 • SLC • ELC • lymphotoxin

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