Engagement of the CD4 receptor inhibits the interleukin‐2‐dependent proliferation of human T cells transformed by Herpesvirus saimiri

Abstract

Infection with Herpesvirus saimiri, a tumor virus of non-human primates, transformed human CD4+ T cell clones to permanent interleukin (IL)-2-dependent growth without need for restimulation with antigen and accessory cells. The IL-2-dependent proliferation of these cells was dramatically inhibited by soluble anti-CD4 whole antibodies, F(ab')2 and Fab fragments, and also by gp 120 of human immunodeficiency virus. The inhibition was not due to cell death and could be overcome by high concentrations of exogenous IL-2. Cell surface expression of CD4, and to a lesser degree the density of the IL-2 receptor alpha chain, were reduced upon anti-CD4 treatment. After long lasting (> 12 h) incubation with anti-CD4, abundance and activity of CD4-bound p56lck were diminished while the free fraction of p56lck remained unchanged. Since IL-2 binding to its receptor activated only the CD4-bound fraction of p56lck, the IL-2-induced p56lck activity was diminished after long-term CD4 ligation. Taken together, our results suggest a cross talk between CD4- and IL-2 receptor-mediated signaling via p56lck.

Selective Activation of T Cell Kinase p56 by Herpesvirus saimiri Protein Tip

“…Furthermore, the appearance of Lyn in HTLV-I-infected T cells was accompanied by a gradual loss of Lck activity, which correlated with dedifferentiation of these cells to IL-2-independent growth (18). 2 Neither decrease of Lck abundance and activity nor IL-2 independence was ob-2 J. B. Bolen, unpublished observations.…”

“…The ORF2-encoded saimiri transformation-associated protein (StpC) is also expressed in H. saimiri transformed human T cells and might complement the action of Tip. StpC is a strong oncoprotein in rodent fibroblasts and epithelial cells of transgenic mice, but not in T cells (11,12 (2,8). CB15 is a CD4ϩ T cell line derived from cord blood (1), 3C a CD8ϩ T cell line derived from peripheral blood by infection with H. saimiri.…”

Anti-Human CD4 Induces Peripheral Tolerance in a Human CD4+, Murine CD4−, HLA-DR+ Advanced Transgenic Mouse Model

“…This finding indicates that anti-CD4-coated cells in vivo, i.e., in Max.16H5-treated CD4/DR3 mice, would not clonally expand upon Ag presentation. Indeed, Max.16H5 was shown to inhibit IL-2-dependent proliferation of transformed human Th cells (41). Finally, Max.16H5 induces a Th1ϾTh2 cytokine shift in human PBMC (42).…”

Autocrine stimulation of rhadinovirus-transformed T cells by the chemokine CCL1/I-309

“…The growth-transformed human T cells harbor multiple copies of the viral genome as nonintegrated episomes without producing virus particles (Biesinger et al, 1992). Furthermore, the transformed cells retain many essential features of normal T cells, such as surface phenotype, early signal transduction parameters, interleukin-2 (IL-2) dependence, major histocompatibility complex-restricted antigen specificity, inducible cytotoxicity, and cytokine production (Biesinger et al, 1992;Bro¨ker et al, 1993;De Carli et al, 1993;Mittru¨cker et al, 1993).…”

“…The most pronounced phenotypic difference is a CD2-mediated enhanced proliferation of transformed T cells due to stimulation via cell-bound CD58, which is mediated by autocrine IL-2 and IL-3 production (Mittru¨cker et al, 1992;Del Prete et al, 1994). Moreover, unusually high levels of interferon-g (IFN-g) are produced after stimulation, and a shift of transformed cells toward the T H 1 phenotype is observed (Bro¨ker et al, 1993;De Carli et al, 1993). Similar to T cells transformed by human T-cell leukemia virus type 1 (HTLV1), the nonreceptor tyrosine kinase Lyn is aberrantly expressed and enzymatically active in T cells after HVS transformation (Yamanashi et al, 1989;Wiese et al, 1996;Fickenscher et al, 1997).…”