NR2f6 governs immune defense against microbial pathogens

Content of research project: For many viruses effective vaccines exist; classic examples include measles, mumps or rubella. Other viruses, such as HIV, hepatitis C virus (HCV), or hepatitis B virus (HBV) can cause substantial tissue damage in some or all individuals they infect, and lesions can become chronic. These viruses usually have one or more properties that allow them to diminish the efficacy of host immunity. Understanding the underlying molecular mechanisms within the adaptive immune system could in the long run improve vaccination strategies. It is becoming increasingly clear that immune response outputs are orchestrated by several members of the nuclear receptor family including the glucocorticoid, the estrogen or the vitamin-D3 receptor which allow for the fine tuning of immune cellular processes to environmental changes such as external milieu signals and the cell intrinsic metabolic state during host protection. Several lines of evidence suggest that the nuclear receptor NR2F6 is a negative regulator of CD8+ T cell activation responses suppressing key cytokine as well as killing ability in vivo. Therefore in depth analysis of NR2F6 function in nave, effector and memory CD8+ T cells during infection with bacteria as Listeria monocytogeneses is the aim of this research proposal in order to understand protective CD8+ T cell immune responses in more detail. On the long run, this detailed knowledge might provide crucial information of how to modulate CD8+ T cell functions for improving therapy regimens during infections or vaccination in the clinic. Hypotheses: How does NR2F6 suppress TCR signaling thresholds, and which are its direct transcriptional target genes in CD8+ T cells? How does NR2F6 exert its CD8+ T cell intrinsic function during infection models in vivo? Is transient inhibition of Nr2f6 by siRNA-mediated knock down sufficient to modulate anti-pathogen immune responses in mice and, finally which of these roles of NR2F6 are also evident in human CD8+ T cells? Methods: Nr2f6 deficient and transgenic mouse strains, infection with microbial pathogens, analysis of CD8 T cells, determining Nr2f6 target genes, analysis of human CD8 T cells. New and/or special about the project: T lymphocytes represent an important branch of the adaptive immune system that attack and destroy pathogens like bacteria and viruses as well as cancerous cells. Specifically boosting CD8+ T cell responses (by i.e. systemic NR2F6 inhibitor) could enhance anti-pathogen immunity and contribute to enhanced pathogen clearance and enhanced host survival under some circumstances.