Bystander sensitization to activation-induced cell death as a mechanism ofvirus-induced immune suppression

Viral infections which induce strong T-cell responses are often characteriz ed by a period of transient immunodeficiency associated with the failure of host T cells to proliferate in response to mitogens or to mount memory rec all responses to other antigens. During acute infections, most of the activ ated, proliferating virus-specific T cells are sensitized to undergo apopto sis on strong T-cell receptor (TCR) stimulation, but it has not been known why memory T cells not specific for the virus fail to proliferate on exposu re to their cognate antigen. Using a lymphocytic choriomeningitis virus (LC MV) infection model in which LCMV-immune Thy 1.1(+) splenocytes are adoptiv ely transferred into Thy 1.2(+) LCMV carrier mice, we demonstrate here that T cells clearly defined as not specific for the virus are sensitized to un dergo activation-induced cell death on TCR stimulation in vitro. This bysta nder sensitization was in part dependent on the expression of Fas ligand (F asL) on the activated virus-specific cells and gamma interferon (IFN-gamma) receptor expression on the bystander T cells. We propose that Fast from hi ghly activated antiviral T cells may sensitize IFN-gamma-conditioned T cell s not specific for the virus to undergo apoptosis rather than to proliferat e on encountering antigen. This may In part explain the failure of memory T cells to respond to recall antigens during acute and persistent viral infe ctions.