Mechanisms of suppression of cytotoxic T-cell responses in murine lymphocytic choriomeningitis virus infection.

Abstract

The cytotoxic T-cell response to lymphocytic choriomeningitis (LCM) virus infection was suppressed either in vitro or in vivo by addition of a high level of syngeneic virus-infected cells or syngeneic cells from congenital LCM virus carriers to the environment of the responding cells. This effect was not duplicated by formaldehyde-fixed carrier cells, nor could it be accounted for by 'cold' target competition by carrier cells at the level of the cytotoxicity assay. Conversely, suppression was produced in vivo by water-lysed, ultrasonically treated carrier cell suspensions, or by a large dose of LCM virus equivalent to that contained in the carrier cells. Thus a high level of infectious virus was a common factor in all observed examples of suppression. Based upon this, the following hypothesis, a form of 'forbidden clone deletion,' was proposed to account for virus-specific cytotoxic T-cell tolerance in LCM virus congenital carriers, or in high dose suppression. A high level of virus in lymphoid tissues, while not cytopathic per se, may result in infection of all or most T cells; this then may lead to deletion either via 'suicide' of individual, infected, cytotoxic T cells with receptors specific for virus-induced antigenic patterns on their own surface membranes, or by mutual lysis of two adjacent T cells.

The Immune Response of the Mouse to Lymphocytic Choriomeningitis Virus. II. Active Suppression of Cell-mediated Immunity by Infection with High Virus Doses

“…Hence, the underlying mechanisms are probably not related. Our observations also effectively invalidate explanations given in the past for high virus dose survival and related phenomena such as mutual destruction of CTL which are both infected and cytolytic for CTL (Dunlop & Blanden, 1977) and dilution of CTL due to extensive replication of the agent throughout the body resulting in their dissipation in various tissues (Zinkernagel & Doherty, 1979). More probably, the suppression in mice of LCM virus-specific CMI by high virus doses is an expression of immune regulation.…”

“…One exception is the paradoxical survival after infection with high doses of virus (Bengtson & Wooley, 1936;Hotchin & Benson, 1963;Lehmann-Grube, 1969;Suzuki & Hotchin, 1971;Lehmann-Grube et al, 1981 b). Because of similarities between adult mice surviving infection with high virus doses and neonatal or congenital carrier mice, it had been assumed that the underlying mechanisms are related (Suzuki & Hotchin, 1971;Dunlop & Blanden, 1977). The findings to be reported show that this is probably not the case.…”

“…High virus dose survival has been known for over 40 years (Bengtson & Wooley, 1936) and an inverse relationship between virus dose and cytotoxic T cell response had been noted by Doherty et al (1974) and Cihak & Lehmann-Grube (1978) and studied by Dunlop & Blanden (1977). A satisfactory explanation, however, has not been given.…”

Mechanisms of persistence in arenavirus infections: a brief review

“…One report has appeared suggesting that this may be the case (Zinkernagel and Doherty 1974). However, no evidence for cells that mediate suppression of the generation of cytotoxic T cells to LCMV was found by other workers (Dunlop and Blanden 1977;Cihak and Lehmann-Grube 1978) studying LCMV carrier mice.…”

“…Mice that have been infected with LCMV during the neonatal period or in utero become chronic carners of the virus. Little or no LCMV-specific T-cell-mediated cytolytic activity can be demonstrated in these persistently infected mice (Cole et al 1973;Marker and Volkert 1973;Dunlop and Blanden 1977;Cihak and Lehmann-Grube 1978). The lack of reactivity appears to be specific for the persistent virus; carrier mice are quite capable of developing a cytotoxic T cell response against Pichinde virus, another arenavirus (Oldstone 1979).…”