THE FAMILY OF KAPPA B 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 both temporally and in appropriate cell-types for specific genes. We are attempting to elucidate how this specific regulation occurs. In studying the molecular activation of NF-kappaB in nontransformed T cells following stimulation by antigen and antigen-presenting cells (APCs), we found that exposure to APCs alone was sometime sufficient. NF-kappaB induction by APC's alone appeared due to the secretion of TNFalpha. These results thus establish an antigen receptor-independent pathway for the up- regulation of NF-kappaB during T cell activation. 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-kappaC (previously called NF-CYT1) that interacts preferentially with a kappaB site in the interleukin-2 gene. The presence of NF-kappaC 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-kappaC consists of a homodimeric complex of the NF-kappaB 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-kappaC complex is governed by an inhibitory protein (IkappaC) that sequesters the NF-kappaC complex in the nucleus following antigen stimulation. Evidence currently suggests that the inhibitor of the p50 complex may be the proto-oncogene bcl-3, that is found at the breakpoint of chromosomal translocation in specific types of lymphomas.