LYMPHOCYTE SIGNALLING PATHWAYS INVOLVING NUCLEAR FACTOR KAPPA B REGULATORS

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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 related to the mammalian Rel oncogene and the drosophila protein, dorsal. Importantly, the kappaB sequence is found in the human immunodeficiency virus (HIV). We have established a system to 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 TH1 and TH2 subsets of CD4+ T lymphocytes. It is believed that there may be a switch from the TH1 to the TH2 subset in the late course of AIDS. We have therefore been studying the transcriptional activating function of the human immunodeficiency virus long terminal repeat (HIV LTR) which is controlled by NF-kappaB. Our preliminary findings suggest that the HIV LTR is more active in TH2 cells suggesting that viral production might be accelerated in the late phases of AIDS during the TH1 to TH2 switch. Further work will be directed at confirming and extending these findings and determining how various subunits of the NF-kappaB family regulate the binding site within the HIV LTR. One of the most interesting features of antigen signalling in T cells is that the same T cell receptor (TCR) complex can lead to activation, which includes NF-kappaB induction, or to programmed cell death (apoptosis). The signal pathways that discriminate between these two outcomes are unknown. We have initiated studies to systematically mutagenize the cytoplasmic signalling portions of the CD3 and zeta portions of the TCR complex to determine the signalling requirements for activation and death. We have found that the zeta cytoplasmic portion is necessary and sufficient for apoptosis, whereas zeta and the CD3 epsilon intracytoplasmic portion can signal for activation including NF-kappaB induction and IL-2 expression. Further extensive mutagenesis has shown that specific amino acid sequences called "immunoreceptor tyrosine-based activation motifs" (ITAMS) that are present in the cytoplasmic regions of the various signalling chains have differential effects in inducing activation and death.