The T Cell Co-stimulatory Molecule GITR in the Control and Treatment of a Persistent Viral Infection

During persistent viral infections such as human immunodeficiency virus (HIV) in human or lymphocytic choriomeningitis virus (LCMV) in mice, the immune response must achieve a balance between immune control and pathology. CD4 T cell help and co-stimulatory factors remain under-investigated in this context. This thesis explores the role of the Glucocorticoid-Induced Tumour Necrosis Factor Receptor-Related Protein (GITR) and its efficacy as a target for therapy in chronic infection. Mice that lack the T cell co-stimulatory molecule GITR have impaired LCMV-specific CD8 T cell responses and control of chronic LCMV infection. The effects of GITR were lost when mice were depleted of CD4 T cells. GITR directly supports the accumulation of IL-2+ T helper type 1 (Th1) cells, thereby indirectly facilitating early LCMV-specific CD8 T cell responses, late B cell responses, and viral control. In vivo GITR-induced signals were detected at day 3 post-infection, and defects in CD4 T cell accumulation in GITR-deficient T cells were apparent starting at day 5 post-infection. GITR-Ligand (GITRL) is maximally induced on antigen presenting cells at day 2 post-infection, but is downregulated to below baseline levels by day 8 post-infection, and remains so at the chronic stage of infection (day 21 post-infection). GITR expression was highest on regulatory T cells (Tregs) but was also detected on Th1 and LCMV-specific CD8 T cells at day 8 post-infection and was maintained at low levels at day 21 post-infection. As GITRL was limiting at this late time point, we investigated the potential of therapeutic stimulation of GITR using an anti-GITR agonist monoclonal antibody. Anti-GITR treatment at day 21 post-infection increased the frequency and number of LCMV-specific CD8 T cells and improved viral control. These effects of anti-GITR were CD8 T cell-intrinsic. Taken together, this thesis demonstrates that GITR plays an important early role on CD4 T cells to support CD8 T and B cell responses to persistent LCMV infection, but at later time points, anti-GITR therapy acts directly on the CD8 T cells to improve viral control. These studies may inform the development of novel immune therapies for human persistent viral infections as well as malignancies.Ph.D