Cytotoxic T lymphocyte (CTL) mediated killing has classically been associated with a high level of specificity for the target cell. However, when CTL clones and specific target cells were copelleted with innocent bystander cells for which the CTL was not specific, these bystander cells were also lysed. Bystander lysis did not depend on HLA compatibility between effector and bystander cell. Indeed bystander lysis was particularly efficient during cognate synthetic peptide induced CTL-CTL killing. Bystander lysis was species unrestricted. Lytic activity could not be transferred in supernatants nor could it be inhibited by anti-tumor necrosis factor antibodies. Perforin sensitive red blood cells were very inefficiently bystander lysed. Bystander cell death was characterized by DNA fragmentation indicative of apoptosis or programmed cell death. Bystander lysis thus appeared to be due to the apoptotic CTL lytic mediator(s). Importantly, CTL were not resistant to bystander lysis induced by other CTL; nor did they become resistant when they were actively killing target cells. Since it is well established that CTL survive the delivery of their own lytic mediators, these results suggest that CTL induced apoptosis is a membrane mediated event.
The hematopoietic cell lines HL-60 and THP-1 were challenged with hepatitis B virus (HBV) in vitro to study interactions between the virus and host cell. Exposure to HBV suppressed the ability of HL-60 cells to differentiate into granulocytes after treatment with retinoic acid (RA) or dimethyl sulfoxide (DMSO), and RA-induced activation of the monocytic cell line THP-1 was also suppressed. Terminal differentiation of both cell lines by phorbol 12-myristate 13-acetate (PMA) was not affected by HBV. The suppressive effect on RAor DMSO-induced differentiation was unique to HBV, since cell exposure to human cytomegalovirus, another virus that inhibits hematopoiesis, failed to block cellular differentiation. At 5 days postinfection, extracellular viral DNA was detected in immature but not in differentiated cultures and higher levels of core antigen (HBcAg) and surface antigen (HBsAg) were seen in undifferentiated cells than in RAor PMA-treated cells. In addition, release of HBsAg into the medium was 2 to 12 times greater in untreated cultures than for RAor PMA-treated cells. Thus, HBV suppresses hematopoiesis by blocking the maturational development of progenitors and selectively infects immature myeloid cells compared with mature end-stage cells.
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