CD4 T cell-dependent wasting disease during infection with lymphocytic choriomeningitis virus

Lymphocytic choriomeningitis virus (LCMV) is characterized by severe weight loss and is therefore called wasting disease. It is known that LCMV-induced wasting disease results not from viral replication, but instead from the immune response against the virus. However, the antiviral immune functions leading to weight loss during this disease are unknown. To determine the mechanism of wasting disease, we first characterized the CD4 T cell response against LCMV. We found that the induction of large numbers of LCMV-reactive CD4 T cells correlates with the onset of wasting disease, and that a loss of LCMV-reactive CD4 T cells correlates with recovery from wasting. To determine functions of CD4 T cells that contribute to wasting, we identified cytokines produced by LCMV-specific CD4 T cells and tested whether these cytokines play a role in the disease. Adoptive transfer experiments using cytokine deficient cells showed that while TNF-α does not have a detectable role in the disease, IFN-γ contributes to LCMV-induced wasting, most likely through its ability to enhance APC function by inducing MHC class II expression within the central nervous system (CNS). We found that IL-1 receptor deficient mice did not lose weight after LCMV infection, and IL-6 deficient mice showed decreased severity of wasting following infection, indicating that the IL-1 receptor is required for wasting and that IL-6 contributes to wasting. By examining several factors that are known to directly regulate appetite, we additionally found that levels of the appetite suppressor α-MSH are increased in the brain during wasting, identifying α-MSH as a potential mediator of weight loss during this disease. Our work suggests that these inflammatory cytokines cause wasting by ultimately suppressing food and water intake, possibly through the action of α-MSH. These results illustrate a mechanism by which the immune response against a virus can cause wasting disease. Our findings may also apply to a range of other pathogenic infections where weight loss is a symptom. (Abstract shortened by UMI.)...