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Original Article

Alymphoplasia (aly)-Type Nuclear Factor B–Inducing Kinase (Nik) Causes Defects in Secondary Lymphoid Tissue Chemokine Receptor Signaling and Homing of Peritoneal Cells to the Gut-Associated Lymphatic Tissue System

^a Department of Medical Chemistry, Faculty of Medicine,
^b Center for Molecular Biology and Genetics, Kyoto University, Kyoto 606-8501, Japan
Department of Medical Chemistry, Faculty of Medicine, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan.81-75-753-438881-75-753-4371

honjo{at}mfour.med.kyoto-u.ac.jp

Alymphoplasia (aly) mice, which carry a point mutation in the nuclear factor B–inducing kinase (NIK) gene, are characterized by the systemic absence of lymph nodes and Peyer's patches, disorganized splenic and thymic architectures, and immunodeficiency. Another unique feature of aly/aly mice is that their peritoneal cavity contains more B1 cells than normal and aly/+ mice. Transfer experiments of peritoneal lymphocytes from aly/aly mice into recombination activating gene (RAG)-2^–/– mice revealed that B and T cells fail to migrate to other lymphoid tissues, particularly to the gut-associated lymphatic tissue system. In vivo homing defects of aly/aly peritoneal cells correlated with reduction of their in vitro chemotactic responses to secondary lymphoid tissue chemokine (SLC) and B lymphocyte chemoattractant (BLC). The migration defect of aly/aly lymphocytes was not due to a lack of expression of chemokines and their receptors, but rather to impaired signal transduction downstream of the receptors for SLC, indicating that NIK is involved in the chemokine signaling pathway known to couple only with G proteins. The results showed that the reduced serum levels of immunoglobulins (Igs) and the absence of class switch to IgA in aly/aly mice are due, at least in part, to a migration defect of lymphocytes to the proper microenvironment where B cells proliferate and differentiate into Ig-producing cells.

Key Words: RAG-2^–/– mice • peritoneal cavity cell transfer • lamina propria • IgA plasma cells • chemotaxis assay

Abbreviations used in this paper: aly, alymphoplasia; BLC, B lymphocyte chemoattractant; BLR1, Burkitt's lymphoma receptor 1; BM, bone marrow; CCR, CC chemokine receptor; ELC, EBV-induced molecule 1 ligand chemokine; FDC, follicular dendritic cell; GALT, gut-associated lymphatic tissue; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GC, germinal center; LT, lymphotoxin; LP, lamina propria; MLN, mesenteric LN; NF-B, nuclear factor B; NIK, NF B–inducing kinase; PEC, peritoneal cavity; PP, Peyer's patch; RAG, recombination activating gene; SLC, secondary lymphoid tissue chemokine.

© 2000 The Rockefeller University Press

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