THE FAMILY OF KB 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, kB. 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 kB sequence is found in the human immunodeficiency virus (HIV). A cardinal feature of the kB sequence is that it permits transcription in a highly regulated fashion both 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-kB and another gene regulatory protein called SRF. We have also found that the microheterogeneity in DNA sequence among kB sites has regulatory significance. By studying normal non-transformed T lymphocyte clones we discovered a novel nuclear complex, termed NF-kC (previously called NF-CYT1) that interacts preferentially with a kB site in the interleukin-2 gene. The presence of NF-kC 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. We have shown that NF-kC consists of a homodimeric complex of the NF-kB p50 subunit and that it can directly repress the function of the IL-2 promoter. 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. Importantly, we have found that the binding activity of the NF-kC complex is governed by an inhibitory protein (IkC) that sequesters the NF-kC complex in the nucleus following antigen stimulation. Efforts are underway to molecularly clone the IkC molecule.