Lymphocytes lacking IκB-α develop normally, but have selective defects in proliferation and function

NF-kappaB has been implicated in the development, activation, and function of B and T lymphocytes. We have evaluated the in vivo effects of deletion of I kappaB-alpha, a major inhibitor of NF-kappaB, on lymphocyte development, proliferation, and function. To elucidate the long term role of I kappaB-alpha ill lymphocytes, fetal liver cells of 14.5-day-old I kappaB-alpha (-/-) or wild-type embryos were transplanted into irradiated recombinase-activating gene-2-deficient mice. Within 4 wk, the I kappaB-alpha (-/-) fetal li, er cells reconstitute mature E and T cell populations in the recipients comparable to those produced by wild-type fetal liver cells, However, the proliferative responses of I kappaB-alpha (-/-) B cells are enhanced, whereas those of I kappaB-alpha (-/-) T cells are reduced. The levels of IgG1, IgG2a, IgA, and IgE produced by I kappaB-alpha (-/-) B cells are elevated relative to those produced by I kappaB-alpha (+/+) Or I kappaB-alpha (+/-). Moreover, the specific immune responses to OVA and the generation of germinal centers are impaired in recipients of I kappaB-alpha (-/-) fetal liver cells, These results indicate that I kappaB-alpha plays a vital role in signal transduction pathways regulating lymphocyte proliferation and also in the production of specific Ig isotypes.