Alymphoplasia (aly)-type nuclear factor kappaB-inducing kinase (NIK) causes defects in secondary lymphoid tissue chemokine receptor signaling and homing of peritoneal cells to the gut-associated lymphatic tissue system.
Alymphoplasia (aly) mice, which carry a point mutation in the nuclear factor kappaB-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.
Fagarasan
S
S
Department of Medical Chemistry, Faculty of Medicine, Kyoto University, Kyoto, Japan.
Shinkura
R
R
Kamata
T
T
Nogaki
F
F
Ikuta
K
K
Tashiro
K
K
Honjo
T
T
D000818:Animals; D018925:Chemokines / Q000378:metabolism; D002633:Chemotaxis; D004268:DNA-Binding Proteins; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis; D007421:Intestine, Small / Q000276:immunology*; D008198:Lymph Nodes / Q000002:abnormalities; D008221:Lymphoid Tissue / Q000002:abnormalities*; D051379:Mice; D008817:Mice, Mutant Strains; D010537:Peritoneum / Q000166:cytology / Q000276:immunology*; D010581:Peyer's Patches / Q000002:abnormalities; D010950:Plasma Cells; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D019707:Receptors, Chemokine / Q000378:metabolism*; D015398:Signal Transduction; D000097782:NF-kappaB-Inducing Kinase
D018925:Chemokines; D004268:DNA-Binding Proteins; D007132:Immunoglobulin Isotypes; D017346:Protein Serine-Threonine Kinases; D019707:Receptors, Chemokine; D000097782:NF-kappaB-Inducing Kinase; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2