On the role of glucocorticoid signaling in the differentiation of virus-specific CD8+ T cell memory

We show that signaling through the glucocorticoid receptor, NR3C1, regulates CD8+ T cell memory differentiation. An analysis of single cell RNASeq (scRNASeq) dataset of virus-specific CD8+ T cells revealed lower NR3C1 activity within the cluster exhibiting higher expression of memory CD8+ T cell associated genes. Dexamethasone exposure of antigen-stimulated CD8+ T cells increased the representation of memory precursors within the pool of activated cells both in vitro and in vivo during the acute phase of a resolving infection, thus elevating the pool of persisting memory. RNAseq and biochemical analysis performed on dexamethasone exposed CD8+ T cells revealed a modulation of intrinsic programming resulting in metabolic alteration, lower ROS accumulation and enhanced levels of Bcl2 expression that promoted transition of effectors into memory cells. The phenomenon was evident at a low dose of dexamethasone as higher doses caused mitochondrial toxicity. We, therefore, identify NR3C1 as a modulator of memory CD8+ T cell differentiation and provide a putative strategy for increasing the pool of anti-viral CD8+ T cell memory. C57BL/6 mice were intraperitoneally infected with MHV-68-SIINFEKL and either given sham treatment with the diluent or given 10mg/kg body weight dexamethasone intraperitoneally from 4 to 6 days post infection. The animals were then sacrificed at 8 days post infection and CD8+CD44+ cells were sorted from each group. Samples from 12 mice were pooled into one sample for RNA isolation and sequencing. We then performed pathway enrichment analysis to elucidate the pathways affected within the responding CD8+ T cells upon dexamethaone treatment.