Abnormal immune function of hemopoietic cells from alymphoplasia (aly) mice, a natural strain with mutant NF-kappa B-inducing kinase

Alymphoplasia (aly) mice, a natural strain with a mutant NF-kappa B-inducin g kinase (NIK) gene, manifest a unique phenotype; they lack lymph nodes and Peyer's patches, have a disturbed spleen architecture, and exhibit defects in both Ab and cellular immune responses. Although a stromal defect caused by impaired lymphotoxin-beta receptor signaling accounts for their abnorma l lymphoid organogenesis, the exact mechanisms underlying the development o f immunodeficiency in aly mice are poorly understood. We therefore investig ated the contribution of hemopoietic cells with the aly NIK mutation to the development of immunodeficiency. Transfer of aly/aly bone marrow cells int o aly/+ mice resulted in poorly developed B cell follicles and lack of supp ort for the development of germinal centers and isotype switching, indicati ng that the hemopoietic cells of aly mice contain an autonomous defect. How ever, follicular dendritic cell clusters were maintained in the spleens of these bone marrow chimeras, suggesting that the lack of follicular dendriti c cell clusters in aly mice is probably due to the stromal defect, The aly mice larked marginal zone B cells in their spleens, and aly/aly B cells sho wed an impaired proliferative response after in vitro stimulation. IL-2 pro duction by activated T cells was also impaired. By contrast, the dendritic cells of aly mice exhibited grossly normal development and function. Suppor ting the concept of an autonomous cell defect, Rel protein expression was a ltered in aly/aly spleens. Thus, the aly NIK mutation affects hemopoietic c ell function in an intrinsic fashion and, together with the stromal defect, may contribute to the development of immunodeficiency in aly mice.