Publications (2)9.2 Total impact
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Article: Alterations in gene expression associated with stepwise acquisition of malignancy in murine cytotoxic T cell lines.
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ABSTRACT: We have isolated a series of variant cell lines from a murine CD8+ T cell clone representing distinct stages in stepwise acquisition of malignancy. A first type of variant has acquired independency of restimulation with MHC/Ag but has kept dependence on IL-2 for continuous growth in culture. A second type of variant has acquired, in addition, independency of IL-2. A third type of variant was isolated from tumors induced upon injection of IL-2 independent variants into syngeneic mice. Clonal relatedness between the cell line was ascertained by Southern blot and sequence analyses of their TCR beta chain genes. The cell lines were analyzed for their expression of genes typical for CD8+ T cells, using Northern blot hybridization, flow cytometry, and functional methods. Concentrating on the transition from IL-2 dependent to IL-2 independent cellular growth, we find the same triad of changes in two independently derived groups of variant cell lines: loss of expression of the CD8 alpha gene with concomitant loss of CD8 from the cell surface, a slight but significant overexpression of IL-2R alpha and beta chains with increased low affinity IL-2 binding sites, and constitutive overexpression of c-myc. Autocrine IL-2 dependent growth could be excluded. Expression of p56lck did not vary between the cell lines. We discuss the possibility that IL-2 independent growth may be associated with intracellular redistribution of p56lck from CD8 alpha to IL-2R beta, thus generating constitutively active IL-2R. Ex vivo established tumor variants differed from their parental culture cell lines by their constitutive secretion of IFN-gamma.(ABSTRACT TRUNCATED AT 250 WORDS)International Immunology 10/1993; 5(9):1075-83. · 3.41 Impact Factor -
Article: Affinity enhancement and transmembrane signaling are associated with distinct epitopes on the CD8 alpha beta heterodimer.
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ABSTRACT: CD8 is a heterodimeric membrane glycoprotein on MHC class I-restricted T lymphocytes that cooperates with the alpha beta CD3 TCR in the recognition of MHC class I molecules presenting antigenic peptides. Co-operation has two components: enhancement of the affinity of MHC/peptide-TCR interaction, and signal transduction through the T cell membrane. The cytolytic function of CTL is primarily dependent on the affinity-enhancement component of CD8-TCR cooperation whereas activation of resting CD8+ T cells is primarily dependent on transmembrane signaling. Using a panel of mAb, two to the alpha-chain and three to the beta-chain of CD8, we investigated the relationships between epitopes and functional regions of the CD8 molecule. Two of the antibodies, one to the alpha-chain and one to the beta-chain of CD8, inhibit the cytolytic function of CTL but not the generation of CTL from resting T cells. Another two antibodies, also one to the alpha- and one to the beta-chain, inhibited the generation of CTL while enhancing the cytolytic function of CTL. These results suggest that both the alpha- and beta-chain of CD8 possess two distinct regions, one involved in affinity enhancement and the other in transmembrane signaling. The former may be the MHC class I-binding region whereas the latter may associate with the alpha beta CD3 TCR. The data can explain the apparent functional equivalence of CD8 alpha alpha homodimers and alpha beta heterodimers.The Journal of Immunology 11/1991; 147(7):2075-81. · 5.79 Impact Factor
