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