Hepatitis C Virus Infection Inhibits a Src-kinase Regulatory Phosphatase and Reduces T Cell Activation in vivo.
T-cell Receptor (TCR) signaling occupies a central role in adaptive immune responses. How dysregulation of T cell signaling is achieved in certain cases such as a viral infection has been a matter for investigation. Hepatitis C virus is known to cause persistent infection in the majority of infected people by evading the host innate and adaptive immune responses via mechanisms not clearly understood. Studies have identified virus-derived small RNAs (vsRNAs) in HCV-infected cells to contribute to persistent infections but the biological significance is unclear.
A recent study by Bhattarai N, et al (2017) has shown that HCV infection inhibits a certain kinase regulatory phosphatase (PTPRE) that has been known to activate signaling by the Src family of tyrosine kinases. Activating Src kinase signaling happens to be one of the early TCR signaling events critical in TCR activation and if inhibited, may contribute towards HCV (infection) persistence. The authors have studied the effect of HCV infection on PTPRE expression in this study along with examining TCR mediated activation using PBMCs from patients.
TCR receptor mediated activation was performed using PBMCs (from HCV-negative donors) re-suspended in serum obtained from HCV-infected donors before or after curative HCV therapy. Cells were stimulated with either viral T-cell antigenic pooled peptides with sequences derived from CMV, EBV, and influenza (CEF peptides obtained from AnaSpec, EGT Group) or anti-CD3. TCR-mediated signaling was determined 16 hours post-TCR stimulation by measuring IL-2 or activated Lck proteins.
The authors interpret that HCV containing serum inhibits both antigen-specific (CEF-mediated) TCR signaling and PTPRE expression from data showing that incubation of PBMCs in HCV infected/RNA positive patientís serum reduced IL-2 release following both antigen-specific T cell receptor and anti-CD3 stimulations Figure 1.
Overall findings show that HCV containing serum inhibits both antigen-specific (CEF-mediated) TCR signaling, and one HCV vsRNA arising from the E2 coding region reduces expression of a Src-kinase regulatory phosphatase (PTPRE) both in hepatocytes and lymphocytes in vitro leading to impaired T cell function. This study provides novel insights into antigen-specific and non-specific modulation of T cells by HCV RNA.
Citation: Bhattarai N, McLinden JH, Xiang J, Mathahs MM, Schmidt WN, et al. (2017) Hepatitis C virus infection inhibits a Src-kinase regulatory phosphatase and reduces T cell activation in vivo. PLOS Pathogens 13(2): e1006232. doi: 10.1371/journal.ppat.1006232