I B I B deficiency reveals that a critical NF- B dosage is required for lymphocyte survival

In most cells, the NFB transcription factor is sequestered in the cytoplasm by interaction with inhibitory proteins, the I Bs. Here, we show that combined I B I B deficiency in mice leads to neonatal death, elevated B binding activity, overexpression of NFB target genes, and disruption of lymphocyte production. In I B I B -deficient fetuses, B220 IgM B cells and single-positive T cells die by apoptosis. In adults, I B / I B / reconstituted chimeras exhibit a nearly complete absence of T and B cells that is not rescued by cotransfer with wild-type bone marrow. These findings demonstrate that I Bs tightly control NFB activity in vivo and that increased NFB activity intrinsically impairs lymphocyte survival. Because reduction or rise of NFB activity leads to similar dysfunction, they also reveal that only a narrow window of NFB activity is tolerated by lymphocytes.