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 family of nuclear proteins, which are related to the mammalian Rel oncogene and the drosophila protein, dorsal, that control transcription of these genes. Importantly, the kappaB sequence is found in the human immuno-deficiency 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 T lymphocytes. We study NF-kappaB in nontransformed T cell clones following stimulation by antigen and antigen-presenting cells (APCs). Recently we have focused on comparing the regulation of various NF-kappaB subunits in the T/H1 and T/H2 subsets of CD4+ T lymphocytes. Evidence has suggested that there is a switch from the T/H1 to the T/H2 subset in the late course of AIDS. We have therefore studied the activation of the HIV long terminal repeat (HIV LTR) which is controlled by NF-kappaB. Our preliminary findings suggest that the HIV LTR is more active in T/H2 cells suggesting that viral production might be accelerated in the late phases of AIDS during the T/H1 to T/H2 switch. Further work will be directed at confirming and extending these findings and determining the molecular events responsible for this effect. We have also found that the microheterogeneity in DNA sequence among kappaB sites has regulatory significance. We have discovered a novel nuclear complex, termed NF-kappaC 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 IkappaC inhibitor may be the proto-oncogene bcl-3, that is found is found at the breakpoint of chromosomal translocation in specific types of lymphomas.