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 in the immune response depend on a 10 bp DNA sequence termed, KappaB. This sequence binds a growing family of nuclear proteins, several of which are related to the rel oncogene, 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 the IL-2 receptor alpha chain gene enhancer acts specifically in T cells through cooperation of NF-KappaB and another gene regulatory protein called SRF. We have also found that the microheterogeneity in DNA sequence among KappaB sites has regulatory significance. By studying normal non-transformed T lymphocyte clones we discovered a novel nuclear complex, termed NF-CYT1 that interacts preferentially with a KappaB site in the interleukin-2 gene. Tbe 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. We also have determined that activation of NF-KappaB can occur during antigenic stimulation of T cells independently of T cell receptor signalling.