Polyclonality of the Cytotoxic T Lymphocyte Response to Virus Infection

Abstract

For many years, it has been known that certain viral infections induce a polyclonal B cell activation that can lead to the generation of antibody against self-antigens and nonviral foreign antigens (1–8). More recently, it has been shown that viruses can also be potent polyclonal cytotoxic T lymphocyte (CTL) inducers, spontaneously stimulating the generation of high levels of allospecific CTL (9, 10) and reactivating memory CTL specific for unrelated viruses from previous infections (11). Virus-induced stimulation of self-reactive or “autoimmune” CTL has also been reported in some systems (12–14). Stimulation of allospecific CTL has been observed in humans during episodes of acute infectious mononucleosis (Epstein-Barr virus [EBV] infection) (10, 15, 16) and in the mouse during acute infections with lymphocytic choriomeningitis virus (LCMV), vaccinia virus (VV), Pichinde virus, and murine cytomegalovirus (11). One might expect that acute viral infections would, therefore, be detrimental to allograft survival, and clinical studies have correlated allograft rejections with influenza and cytomegalovirus infections (17–19). Because the primary function of the immune system is to protect the host from infection, it is interesting to speculate whether the allospecific CTL contribute to the control of viral infection or whether they are an incidental byproduct of the antigen-specific response to virus.

In the case of polyclonal B cell stimulation, proliferation is often due to stimulatory or transforming properties of the viral proteins and may not contribute to viral clearance. EBV infection causes a true transformation of B cells (1), whereas the glycoproteins of Sindbis, influenza, and vesicular stomatitis viruses can be mitogenic to B cells, at least in vitro (3–5). Activated T cells and the cell growth and differentiation factors they secrete cause in vitro bystander stimulation of resting B cells that are not specific for the initial inducing antigen (20). Although polyclonally stimulated B cells do not appear to be involved in clearance of viral infection via antigen-specific antibody production, they have been associated with autoimmune phenomena. For example, EBV-transformed B cells produce anti-nuclear and rheumatoid factor antibodies (21).