RESUMO
Chronic hepatitis B virus (HBV) infection affects 300 million patients worldwide1,2, in whom virus-specific CD8 T cells by still ill-defined mechanisms lose their function and cannot eliminate HBV-infected hepatocytes3-7. Here we demonstrate that a liver immune rheostat renders virus-specific CD8 T cells refractory to activation and leads to their loss of effector functions. In preclinical models of persistent infection with hepatotropic viruses such as HBV, dysfunctional virus-specific CXCR6+ CD8 T cells accumulated in the liver and, as a characteristic hallmark, showed enhanced transcriptional activity of cAMP-responsive element modulator (CREM) distinct from T cell exhaustion. In patients with chronic hepatitis B, circulating and intrahepatic HBV-specific CXCR6+ CD8 T cells with enhanced CREM expression and transcriptional activity were detected at a frequency of 12-22% of HBV-specific CD8 T cells. Knocking out the inhibitory CREM/ICER isoform in T cells, however, failed to rescue T cell immunity. This indicates that CREM activity was a consequence, rather than the cause, of loss in T cell function, further supported by the observation of enhanced phosphorylation of protein kinase A (PKA) which is upstream of CREM. Indeed, we found that enhanced cAMP-PKA-signalling from increased T cell adenylyl cyclase activity augmented CREM activity and curbed T cell activation and effector function in persistent hepatic infection. Mechanistically, CD8 T cells recognizing their antigen on hepatocytes established close and extensive contact with liver sinusoidal endothelial cells, thereby enhancing adenylyl cyclase-cAMP-PKA signalling in T cells. In these hepatic CD8 T cells, which recognize their antigen on hepatocytes, phosphorylation of key signalling kinases of the T cell receptor signalling pathway was impaired, which rendered them refractory to activation. Thus, close contact with liver sinusoidal endothelial cells curbs the activation and effector function of HBV-specific CD8 T cells that target hepatocytes expressing viral antigens by means of the adenylyl cyclase-cAMP-PKA axis in an immune rheostat-like fashion.
Assuntos
Linfócitos T CD8-Positivos , Hepatite B Crônica , Fígado , Animais , Humanos , Masculino , Camundongos , Linfócitos T CD8-Positivos/enzimologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Modulador de Elemento de Resposta do AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Vírus da Hepatite B/imunologia , Hepatite B Crônica/imunologia , Hepatite B Crônica/virologia , Hepatócitos/imunologia , Hepatócitos/virologia , Fígado/imunologia , Fígado/virologia , Fosforilação , Transdução de Sinais , Ativação LinfocitáriaRESUMO
The clinical burden of mental illness, in particular schizophrenia and bipolar disorder, are driven by frequent chronic courses and increased mortality, as well as the risk for comorbid conditions such as cardiovascular disease and type 2 diabetes. Evidence suggests an overlap of molecular pathways between psychotic disorders and somatic comorbidities. In this study, we developed a computational framework to perform comorbidity modeling via an improved integrative unsupervised machine learning approach based on multi-rank non-negative matrix factorization (mrNMF). Using this procedure, we extracted molecular signatures potentially explaining shared comorbidity mechanisms. For this, 27 case-control microarray transcriptomic datasets across multiple tissues were collected, covering three main categories of conditions including psychotic disorders, cardiovascular diseases and type II diabetes. We addressed the limitation of normal NMF for parameter selection by introducing multi-rank ensembled NMF to identify signatures under various hierarchical levels simultaneously. Analysis of comorbidity signature pairs was performed to identify several potential mechanisms involving activation of inflammatory response auxiliarily interconnecting angiogenesis, oxidative response and GABAergic neuro-action. Overall, we proposed a general cross-cohorts computing workflow for investigating the comorbid pattern across multiple symptoms, applied it to the real-data comorbidity study on schizophrenia, and further discussed the potential for future application of the approach.