TIM-3 signaling pathways in T cell exhaustion

Chronic viral infections such as human immunodeficiency virus (HIV) as well as cancer are diseases characterized by exhaustion of virus or tumor-specific T cells. Exhausted CD4 + and CD8 + T cells are defined by their loss of effector functions including reduced proliferative capacity, cytokine production and cytotoxicity. These functions are important for a successful immune response against pathogens and cancer and thus reduced functionality of antigen-specific T cells contributes to the inability of the host to clear an infection or kill tumor cells. The mechanisms leading to T cell exhaustion have not been fully elucidated yet; however, initial studies have identified programmed death-1 (PD-1) as one of the molecules expressed on exhausted T cells. Further studies have confirmed the importance of PD-1 in the maintenance of T cell exhaustion and blocking PD-1 interaction with its ligand PD-L1 has been shown to partially reverse T cell exhaustion leading to improved viral and tumour clearance. Nonetheless, not all exhausted T cells were found to express PD-1 indicating the involvement of other pathways. Interestingly, expression of TIM-3 (T cell immunoglobulin domain, mucin domain), an inhibitory T cell receptor, has been detected on exhausted T cells from HIV and hepatitis C virus patients, as well as murine T cells isolated from chronically infected mice or tumor bearing-hosts. Additionally, TIM-3 blockade has been shown to improve the functionality of exhausted T cells, both in humans and animal models, leading to increased cytokine production and proliferation. Thus, TIM-3 has been shown to be involved in the exhaustion of T cells occurring during chronic viral infection and cancer. The proposed aim of this project is therefore to analyze the signaling pathways initiated downstream of TIM-3 ligation thus identifying new signal transducers involved in T cell exhaustion. Specifically, I will be generating inducible transgenic mice expressing BAT3 (HLA-B associated transcript 3), a molecule which has been shown to bind to the tail of TIM-3 and negatively regulate TIM-3 signaling. These mice will allow analysis of the role of the TIM-3/BAT3 signaling axis during chronic viral infection and tumor immunity hence providing important clues about the role of these molecules in T cell exhaustion, such as seen in HIV. Additionally, potential new signal transducers of TIM-3 will be identified by peptide immunoprecipitation using peptides of conserved motifs in the cytoplasmic tail of TIM-3. The information gained by this study will help elucidate the TIM-3 signaling pathway and identify new therapeutic targets needed for the treatment of chronic viral diseases as well as cancer.