CD4 T Cells modulate the protective vs. pathologic response of CD8 T cells during viral infection

Abstract

Vaccines expressing pathogen T cell epitopes have been a widely pursued strategy for improving the efficacy of vaccines against persistent viral infections such as HIV. However, selectively engaging T cells also has the potential to increase rather than prevent pathology, consequently shifting a mild disease to a lethal one after subsequent infection. Thus, determining the immune and viral parameters that lead to protection versus those that mediate pathology is critical for developing a safe and effective vaccine against persistent viral infections. Using lymphocytic choriomeningitis virus (LCMV) and an in vivo adoptive transfer mouse model, we investigated how the precursor frequency of CD8 T cells affected the balance of protection vs. pathology during chronic viral infection. We found that the balance is based largely on the number of T cells responding to the pathogen. Intermediate numbers of responding CD8 T cells results in maximum pathology while high numbers provide full protection. We also looked at CD4 T cells and unlike CD8 T cells, increasing the number of pathogen specific CD4 T cells never provides a protective response and instead leads to high host mortality. We have now begun to study the interaction of CD8 and CD4 T cells simultaneously during viral infection to determine the effects of CD4 T cells on CD8 T cell protective versus pathologic vaccine-induced immunity and what exactly mediates such responses.