Bystander Sensitization to Activation-Induced Cell Death as a Mechanism of Virus-Induced Immune Suppression

In 1908 von Pirquet reported that individuals acutely infected with measles virus failed to mount a delayed-type hypersensitivity reaction to tuberculin even though they had been previously immunized (35). After resolution of the infection, responsiveness to this memory recall antigen returned. Similar types of transient immune deficiencies have subsequently been reported during many viral infections, including those caused by Epstein-Barr virus, cytomegalovirus, and human immunodeficiency virus (HIV) in humans and by lymphocytic choriomeningitis virus (LCMV) in the mouse model (7, 21, 25, 27). In addition to the failure to respond to memory recall antigens, T cells from infected individuals fail to proliferate in response to signals delivered via the T-cell receptor (TCR) by mitogenic lectins, superantigens, or anti-CD3 antibody. In several infections, this transient immune deficiency has been correlated with the induction of apoptosis in the highly activated T cells, which express CD95 (Fas) and CD95 ligand (FasL) (1, 7, 21, 25). Apoptosis by activation-induced cell death (AICD) is now a well-characterized feature of activated T-cell populations that become strongly signaled through their TCR. The interaction of Fas with FasL after TCR stimulation causes Fas to associate with the intracytoplasmic Fas-activated death domain, which initiates the apoptotic pathway (16). Recent work has shown that most of the T cells proliferating in response to viral infections are highly activated virus-specific cells, which would be expected to eventually undergo AICD on appropriate signalling (9, 23). This would explain the failure of the virus-induced T-cell population to respond to nonspecific T-cell mitogens, but this observation does not explain why memory T cells should have deficient responses to their specific cognate antigens. These deficient memory responses might be a consequence of a dilution of memory cells by the proliferating virus-specific cells, of a redistribution of memory T cells such that they are no longer present in the peripheral blood or spleen populations used for testing their function, or of the action of immunosuppressive factors which inhibit their ability to function. Alternatively, as shown here, these non-virus-specific T cells may become sensitized in a bystander fashion to undergo AICD on receptor stimulation. The distinctions between virus-specific and nonvirus-specific T cells can be blurred because many memory T cells can be stimulated during viral infections by cross-reactive interactions (29). We have therefore developed models to clearly identify, in the same systems, T cells that are specific and those that are not specific for viral antigens (38). In this way, one can ask whether bystander events occurring as a consequence of the T-cell response to viral infections alter the activity of T cells whose receptors are not being triggered by the virus. We have used the highly defined LCMV infection of the mouse to explore these processes. The acute LCMV infection is associated with a marked expansion of the CD8 T-cell population, and most of the activated T cells during the LCMV infection are virus specific (23, 25, 29, 38). Between 6 and 12 days postinfection, the host undergoes a transient but severe state of immune deficiency characterized by impaired proliferative response in vitro and by the induction of apoptosis in those T cells (25). This immune deficiency, however, is not found in mice harboring persistent LCMV infection as a consequence of congenital infection. Those persistently infected “LCMV carrier” mice clonally delete their LCMV-specific T cells but can make normal T-cell responses to other antigens (11, 14). If T cells from Thy 1.1+ LCMV-immune mice are transferred into the tolerant Thy 1.2+ carrier mice, they proliferate in response to the viral antigens present, but the host cells, which cannot respond to LCMV antigens, do not increase in number (11, 12, 38). This model can therefore be used to ask how a vigorous antiviral T-cell response can affect the biology of T cells defined as being virus nonspecific but nevertheless coexisting in this milieu. Here we show that a potent antiviral T-cell response causes T cells not participating in the immune response to undergo AICD rather than to proliferate on TCR stimulation. This bystander sensitization to AICD may explain the immunosuppression that follows infections with many viruses.