Mechanism Of T Cell Mediated Hemorrhagic Disease During Lcmv Infection

Abstract T cells are essential in controlling and clearing viral pathogens, but they also have the potential to induce immunopathology. We have previously shown that this balance between protection and pathology is dependent on the number of virus-specific T cells. Specifically, intermediate numbers of CD8 T cells result in lethal hemorrhagic disease, while lower doses result in exhaustion, and higher doses in viral clearance. Increasing the number of virus-specific CD4 T cells also leads to lethal hemorrhagic disease, however the mechanism by which T cells mediate this pathology remains unclear. Using lymphocytic choriomeningitis virus (LCMV) and an in vivo adoptive transfer mouse model, we found that lethal pathology induced by CD8 T cells is dependent on tumor necrosis factor (TNF). The absence of TNF signaling abrogates pathology without impeding viral clearance. Interestingly, CD4 T cell induced pathology, while dependent on CD8 T cells, still occurs in the absence of TNF. Furthermore, IL-2 produced by CD4 T cells modulates CD8 T cell responses to generate hemorrhagic disease that is TNF-dependent. Our findings show that TNF plays a significant role in T cell mediated hemorrhagic disease, and further implies that CD4 T cells modulate CD8 T cells to follow a different mechanism of pathology in the absence of this potent pro-inflammatory cytokine.