Influence of check-point inhibitors on virus-specific T cell receptor repertoires

• Applicant: Dr. Anke Kraft
• Subject Area: Immunology ; Virology
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 319609257

Chronic virus infections and cancer represent major threats to human health. Development of dysfunctional and exhausted T cell responses is characteristic in chronic virus infections and cancer and strongly associated with enhanced expression of co-regulatory molecules e.g. PD-1 and CTLA-4. Blocking co-regulatory molecules by using monoclonal antibodies (called check-point inhibitors, e.g. nivolumab, pembrozumab and ipilimumab) is a current approach to overcome impaired immune responses in cancer. The outcome of this treatment results in highly individual clinical benefits. In chronic virus infection interfering with checkpoint inhibitors is able to rescue functional virus-specific T cell response resulting in reduced virus load or clearance. Beside these promising treatment success in cancer and chronic infection it remains unclear why the treatment responses are so highly diverse between individuals. Also it is unclear which immunological consequence rescued T cells have on a sequential homologous and heterologous virus infection and in the establishment of autoimmunity. In this grant proposal I hypothesis that interfering with check-point inhibitors during persistent viral infection skews the epitope hierarchy and the T cell receptor repertoire of rescued CD8+ T cells and thereby modulating T cell immunity, which will result in modified outcomes upon sequential homologous or unrelated (heterologous) virus infections. For this study, the well characterized mouse model lymphocytic choriomeningitis virus (LCMV) and Pichinde virus (PV) will be used. After treatment of persistently LCMV infected mice with antibodies against PD-L1 and CTLA-4 the diversity, hierarchy and fitness of rescued LCMV-specific T cells including their T cell receptor repertoires and effector/memory phenotype will be studied. To investigate the immunological consequences of rescued T cell immunity onto homologous and heterologous infection mice will be challenge with homolgous (LCMV) or heterologous (PV) viruses.Based on this fundamental analysis we will be getting important insides in potential mechanisms as well as benefits and risks of a reshaped host immune system especially the reshaped T cell pool of patients treated with antibodies blocking co-regulatory molecules in terms of reinfection and in their potentials to develop autoimmunity. These findings are very important for current therapies approaches especially in terms of personalized medicine.

• DFG Programme: Research Grants
• Cooperation Partner: Professor Dr. Markus Cornberg