Search

Increasing evidence suggests that HIV-1-specific cytotoxic T lymphocytes (CTLs) are a key host immune response to HIV-1 infection. Generation of CTL responses for prevention or therapy of HIV-1 infection has several intrinsic technical barriers such as antigen expression and presentation, the varying HLA restrictions between different individuals, and the potential for viral escape by sequence variation or surface molecule alteration on infected cells. A strategy to circumvent these limitations is the construction of a chimeric T cell receptor containing human CD4 or HIV-l-specific Ig sequences linked to the signaling domain of the T cell receptor [Zeta] chain (universal T cell receptor). CD8+ CTLs transduced with this universal receptor can then bind and lyse infected cells that express surface HIV-1 gp120. We evaluated the ability of universal-receptor-bearing CD8+ cells from a seronegative donor to lyse acutely infected cells and inhibit HIV-1 replication in vitro. The kinetics of lysis and efficiency of inhibition were comparable to that of naturally occurring HIV-l-specific CTL clones isolated from infected individuals. Further study will be required to determine the utility of these cells as a therapeutic strategy in vivo.

Anergy is a mechanism of T lymphocyte tolerance induced by antigen receptor stimulation in the absence of co-stimulation. Anergic T cells were shown to have a defect in antigen-induced transcription of the interleukin-2 gene. Analysis of the promoter indicated that the transcription factor AP-1 and its corresponding cis element were specifically down-regulated. Exposure of anergic T cells to interleukin-2 restored both antigen responsiveness and activity of the AP-1 element., In pursuing the observations of Billingham and colleagues (1) on acquired immunological tolerance, Dresser showed that immunization with deaggregated foreign proteins rendered adult mice unresponsive to subsequent antigenic challenge (2). [...]

Regulation of interleukin-2 (IL-2) gene expression by the p50 and p65 subunits of the DNA binding protein NF-κB was studied in nontransformed [CD4.sup.+] T lymphocyte clones. A homodimeric complex of the NF-κB p50 subunit was found in resting T cells. The amount of p50-p50 complex decreased after full antigenic stimulation, whereasa the amount of the NF-κB p50-p65 heterodimer was increased. Increased expression of the IL-2 gene and activity of the IL-2 κB DNA binding site correlated with a decrease in the p50-p50 complex. Overexpression of p50 repressed IL-2 promoter expression. The switch from p50-p50 to p50-p65 complexes depended on a protein that caused sequestration of the p50-p50 complex in the nucleus., Tumor cell lines have proven vital to the study of gene regulation because they are easily grown and manipulated. However, nontransformed T cells exhibit biological characteristics that are not manifested [...]