Disruption of T cell memory during severe immune suppression results in reactivation of chronic viral infections, such as Epstein Barr virus (EBV) and Cytomegalovirus (CMV). How different subsets of memory T cells contribute to the protective immunity against these viruses remains poorly defined. In this study we examined the compartmentalization of virus-specific, tissue resident memory CD8+ T cells in human lymphoid organs. This revealed two distinct populations of memory CD8+ T cells, that were CD69+CD103+ and CD69+CD103—, and were retained within the spleen and tonsils in the absence of recent T cell stimulation. These two types of memory cells were distinct not only in their phenotype and transcriptional profile, but also in their anatomical localization within tonsils and spleen. The EBV-specific, but not CMV-specific, CD8+ memory T cells preferentially accumulated in the tonsils and acquired a phenotype that ensured their retention at the epithelial sites where EBV replicates. In vitro studies revealed that the cytokine IL-15 can potentiate the retention of circulating effector memory CD8+ T cells by down-regulating the expression of sphingosine-1-phosphate receptor, required for T cell exit from tissues, and its transcriptional activator, Kruppel-like factor 2 (KLF2). Within the tonsils the expression of IL-15 was detected in regions where CD8+ T cells localized, further supporting a role for this cytokine in T cell retention. Together this study provides evidence for the compartmentalization of distinct types of resident memory T cells that could contribute to the long-term protection against persisting viral infections.
We demonstrate mechanochemical regulation of platelet adhesion to von Willebrand factor in thrombosis and hemostasis.
Stress has been implicated in the onset and illness course of schizophrenia and bipolar disorder. The effects of stress in these disorders may be mediated by abnormalities of the hypothalamic-pituitary-adrenal axis, and its corticosteroid receptors. We investigated mRNA expression of the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), and protein expression of multiple GRα isoforms, in the prefrontal cortex of 37 schizophrenia cases and 37 matched controls. Quantitative real-time PCR, western blotting, and luciferase assays were employed. In multiple regression analysis, schizophrenia diagnosis was a significant predictor of total GR mRNA expression (p<0.05), which was decreased (11.4%) in schizophrenia cases relative to controls. No significant effect of diagnosis on MR mRNA was detected. At the protein level, no significant predictors of total GRα protein or the full-length GRα isoform were identified. However, schizophrenia diagnosis was a strong predictor (p<0.0005) of the abundance of a truncated ≈ 50 kDa GRα protein isoform, putative GRα-D1, which was increased in schizophrenia cases (80.4%) relative to controls. This finding was replicated in a second cohort of 35 schizophrenia cases, 34 bipolar disorder cases, and 35 controls, in which both schizophrenia and bipolar disorder diagnoses were significant predictors of putative GRα-D1 abundance (p<0.05 and p=0.005, respectively). Full-length GRα was increased in bipolar disorder relative to schizophrenia cases. Luciferase assays demonstrated that the GRα-D1 isoform can activate transcription at glucocorticoid response elements. These findings confirm total GR mRNA reductions in schizophrenia and provide the first evidence of GR protein isoform abnormalities in schizophrenia and bipolar disorder.
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