HTLV-I gene expression in adult T-cell leukemia cells elicits an NK cell response in vitro and correlates with cell rejection in SCID mice

Abstract

Human T-cell leukemia virus type I (HTLV-I) is the etiologic agent of adult T-cell leukemia (ATL). We have previously shown that the ATL cell line, RV-ATL, formed tumors when inoculated into severe combined immunodeficient (SCID) mice. In contrast, the HTLV-I in vitro-transformed cell line, SLB-I, was nontumorigenic in SCID mice. ATL cells contain HTLV-I proviral DNA sequences but lack detectable viral gene expression, in contrast to HTLV-I in vitro-transformed cells, which express all viral gene products. We investigated the role of HTLV-I gene expression in tumorigenesis by superinfecting RV-ATL cells with HTLV-I. The resulting cell line, HT-1RV, expressed HTLV-I. Injection of HT-1RV cells into SCID mice resulted in a reduced tumorigenic phenotype compared to the parental RV-ATL cells. In vitro natural killer (NK) cell cytotoxicity assays revealed that cell lines expressing HTLV-I gene products, SLB-I and HT-1RV, were sensitive to NK cell cytolysis. In contrast, nonexpressing RV-ATL cells were resistant to NK cell cytolysis. These studies indicate that lack of viral gene expression allows HTLV-I-infected cells to elude detection by murine NK cells and increases tumorigenicity in SCID mice. Thus the loss of HTLV-I gene expression in ATL cells may be an important mechanism by which leukemic cells escape immune surveillance in humans.