Hepatitis C virus core protein up-regulates anergy-related genes and a new set of genes, which affects T cell homeostasis

Abstract

Hepatitis C virus (HCV) infection is the main cause for chronic hepatitis, leading to cirrhosis and hepatic carcinoma. Virally induced immune dysfunction has been called as the cause for viral persistence. Previous results demonstrate that CD4 Jurkat cells stably expressing the HCV core protein show an increased activation of NFAT transcription factor and an impaired IL-2 promoter activity, affecting intracellular signaling pathways in a manner that mimics clonal anergy. We had shown previously that NFAT activates a transcriptional program, ensuing in immunological tolerance. In the present work, we have engineered lentiviral vectors expressing the HCV core to analyze the events, which unfold in the initial phase of HCV core-induced anergy. We show that genes initially described to be up-regulated by ionomycin-induced anergy in mice are also up-regulated in humans, not only by ionomycin but also by HCV core expression. We also show that HCV core is sufficient to cause NFAT nuclear translocation and a slow-down in cell-cycle progression, and using whole genome microarrays, we identify novel genes up-regulated in Jurkat cells expressing HCV core. The relevance of our results is highlighted by the presence of HCV in CD4 T cells from HCV chronically infected patients.

Peripheral blood T cells in acute myeloid leukemia (AML) patients at diagnosis have abnormal phenotype and genotype and form defective immune synapses with AML blasts

“…The gene expression changes seen in AML T cells are not purely due to the normal signaling seen on T-cell activation 26 and not supportive of an anergic state. 27 Our results are in keeping with the hypothesis that both CD4 and CD8 T cells in AML have undergone an aberrant activation process. Comparison of the gene lists with those generated from our previous studies in CLL 4 demonstrated little commonality.…”

“…These data are in keeping with the fact that the gene expression changes seen in T cells from patients with AML are not simply due to the normal signaling that occurs on T-cell activation. A search for 14 anergy-related genes 27 within the AML versus healthy gene lists further revealed the differential expression of only 2 genes, namely JMJD2B and RAB10. These microarray results were validated using qRT-PCR for 5 differentially expressed genes (ACTN1, ATM, CD48, FOSB, and JUN).…”

CD28 and KIR2D receptors as sensors of the immune status in heart and liver transplantation

“…Likewise, HCV core protein is able to downregulate CD4 ϩ lymphocyte responses by inducing anergy through activation of NFAT with no concurrent activation of AP-1 or NF-B [50]. HCV, however, did not alter the allogeneic-induced up-regulation of CD28 or KIR2D molecules in liver recipients from our series, suggesting that molecule downregulation induced by CMV follows specific pathways.…”

HCV Infection Enhances Th17 Commitment, Which Could Affect the Pathogenesis of Autoimmune Diseases

“…However, the results of our two kinds of experiments (plasmids and lenti-virus) consistently showed that the expression of HCV-core protein in T lymphocytes could enhance the Th17 development. Other groups previously reported that HCV-core protein could affect anergy-related genes and T cell responses by inducing spontaneous and alternating T-cell receptor-triggered Ca2+ oscillations[37], [38]. Therefore, the expression of HCV-core protein in T lymphocyte might be important for the functional changes in T lymphocytes.…”