THE FAMILY OF KAPPAB REGULATORS FOR GENES IN THE IMMUNE RESPONSE

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Regulation of genes for several lymphokines as well as other molecules involved immune response depend on a 10 bp DNA sequence termed, kappaB. This sequence binds a growing family of nuclear proteins that are capable of tightly governing transcription of these genes. Importantly, the kappaB sequence is found in the human immunodeficiency virus (HIV). A cardinal feature of the kappaB sequence is that it permits transcription in a highly regulated fashion-temporally and in appropriate cell-types for specific genes. We are attempting to elucidate how this specific regulation occurs. We have found sequences near the kappaB sequence in the IL-2 receptor alpha chain genes modulate its activity. They allow it to respond to the transcription factor NK-kappaB only in T cells. In addition, we have been using a computer program developed by Dr. Ghosh in conjunction with the National Center for Biotechnology Information (National Library of Medicine) to study relationships between gene promoters that contain kappaB sequences to decipher the co-regulatory signals encoded in the DNA. We have also found that the microheterogeneity in DNA sequence among kappaB sites has regulatory significance. We have discovered a novel nuclear factor, termed NF-CYT1 that interacts preferentially with a kappaB site in the interleukin-2 gene. The presence of NF-CYT1 in a number of different biological conditions is inversely correlated with IL-2 gene expression in T cells. This suggests it may be a negative regulator. Very significantly, this factor binds to the enhancer region of HIV. We postulate it may have a role in suppressing HIV viral transcription in resting T cells.