CD8 T cell-intrinsic expression of glucocorticoid receptor (NR3C1) is critical to limit lethal immunopathology during chronic viral infection 4215

Abstract Description During chronic infection, CD8 T cells undergo a progressive loss of function in a process coined T cell exhaustion. Although T cell exhaustion impairs control over viral replication, it may also be important to limit immunopathology. Recent data indicate that exhausted cells are comprised of heterogenous populations, including a progenitor subset that can bifurcate into either terminally exhausted cells or cytolytic effector cells that are crucial for viral control. However, the molecular circuitry underpinning the differentiation of these subsets remains unclear. Using scRNA-seq, we show thatNr3c1 is upregulated in the effector subset during chronic LCMV infection. As glucocorticoid receptor (GR) signaling is typically associated with immunosuppression, we hypothesized that effector cells are tightly regulated by GR signaling. To test this, we employed use of E8iCre x Nr3c1fl/fl mice, which allows for conditional deletion of GR in peripheral CD8 T cells. Remarkably, conditional Nr3c1 KO mice exhibited significant morbidity and mortality following chronic LCMV infection, with 100% of mice succumbing to CD8 T cell-mediated-pathology by day 10 post-infection. Phenotypic and functional characterization revealed that Nr3c1-deleted CD8 T cells displayed augmented production of IFNg, as well as increased expression of GzmB and Eomes compared to WT cells. Collectively, our data show that GR signaling functions to suppress pathological CD8 T cell responses during chronic infection. Funding Sources R00AI153537 Topic Categories Viral Immunology (VIR)