Impact of rat CMV vXCL1 on the interaction between XCR1+ DC and XCL1-producing cells

• Applicant: Professor Dr. Sebastian Voigt
• Subject Area: Virology
• Term: since 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 240143179

The immune system is essential for the defense against pathogens such as viruses. Immune cells involved in that defense include Natural Killer (NK) cells and T lymphocytes, which can recognize and eliminate virus-infected cells. Dendritic cells (DC) represent an important population of cells that can present antigens (e.g., viral antigens) to T lymphocytes to activate them and to act against virus-infected cells. In order for these immune cells to interact and communicate, messenger substances called chemokines are important. One of these chemokines is the gamma chemokine XCL1, which is secreted by NK cells and certain T lymphocytes. This chemokine binds to the receptor XCR1, which is found on the cell surface of a specific DC subtype. This communication, which initially takes place between NK cells and DC, and later between T lymphocytes and DC, is important for combating intracellular pathogens such as viruses. DCs play a bridging role in this process, linking innate with adaptive immunity. Human pathogenic herpesviruses include cytomegalovirus (CMV), which can cause severe complications in immunocompromised individuals. CMV has a large number of genes that the virus uses to evade an immune response, thereby promoting its spread. Because CMV is strictly species-specific and thus infects only humans, studies of immunomodulatory pathways involving viral analogs of immune genes are being conducted in animal models. These models include the rat and rat cytomegalovirus (RCMV). RCMV is the only known virus to possess a gene analogous to the rat gamma chemokine XCL1 that functions in a similar manner to the rat XCL1 chemokine by attracting DC. These studies provide an unique opportunity to gain new insights into the interaction of immune cells such as NK cells, T lymphocytes and DC. A rather novel way to counteract a decrease in effectiveness of T cell responses that can be observed during the course of chronic viral infections or also some tumor diseases is to block the molecule PD-L1 by means of antibody therapy (checkpoint inhibition). However, checkpoint blockade alone does not suffice for the treatment of many tumor diseases, as there is insufficient stimulation of the immune system. Since XCR+ DC amplify the system and contribute to a renewed activation of T lymphocytes, it is expected that the planned studies will also shed light on the human immune system and contribute to a better understanding of checkpoint blockade that can be used therapeutically.

• DFG Programme: Research Grants