Alymphoplasia (aly)-type nuclear factor kappa 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

Alymphoplasia (aly) mice, which carry a point mutation in the nuclear facto r kappa B-inducing kinase (NIK) gene, are characterized by the systemic abs ence of lymph nodes and Peyer's patches, disorganized splenic and thymic ar chitectures, and immunodeficiency. Another unique feature of aly/aly mice i s that their peritoneal cavity contains more B1 cells than normal and aly/ mice. Transfer experiments of peritoneal lymphocytes from aly/aly mice int o recombination activating gene (RAG)-2(-/-) mice revealed that B and T cel ls fail to migrate to other lymphoid tissues, particularly to the gut-assoc iated 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 o f expression of chemokines and their receptors, but rather to impaired sign al transduction downstream of the receptors for SLC, indicating that NIK is involved in the chemokine signaling pathway known to couple only with G pr oteins. 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 l east in part, to a migration defect of lymphocytes to the proper microenvir onment where B cells proliferate and differentiate into Ig-producing cells.