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

Abstract

The rhadinovirus herpesvirus saimiri transforms human T lymphocytes to stable growth in culture. Besides the viral oncogenes stpC and tip, little is understood about the transformation process at the cellular level. To identify cellular factors that might contribute to growth transformation, we compared cellular gene expression in pairs of herpesvirus saimiri-transformed and nontransformed human T-cell clones. Using cDNA arrays and suppressive subtractive hybridization, we were able to identify the chemokine CCL1/I-309 as one of the few cellular genes that are strongly overexpressed in T cells after growth transformation with herpesvirus saimiri. The transformed T cells expressed CCR8, the receptor for CCL1, which rapidly induced intracellular calcium ion levels. Neutralizing antibodies to CCL1 led to reduced secretion of interferon-γ and tumor necrosis factor-α as well as to reduced proliferation rates in transformed T cells. Thus, we propose that growth transformation of human T cells with herpesvirus saimiri gives rise to an autocrine loop where the proliferation of transformed T cells is supported by the endogenous production of the chemokine CCL1.