Pancreatic beta cells persistently infected with coxsackievirus B4 are targets of NK cell-mediated cytolytic activity

Cell Mol Life Sci. 2020 Jan;77(1):179-194. doi: 10.1007/s00018-019-03168-4. Epub 2019 Jun 6.


It has been suggested that the persistence of coxsackieviruses-B (CV-B) in pancreatic beta cells plays a role in the pathogenesis of type 1 diabetes (T1D). Yet, immunological effectors, especially natural killer (NK) cells, are supposed to clear virus-infected cells. Therefore, an evaluation of the response of NK cells to pancreatic beta cells persistently infected with CV-B4 was conducted. A persistent CV-B4 infection was established in 1.1B4 pancreatic beta cells. Infectious particles were found in supernatants throughout the culture period. The proportion of cells containing viral protein VP1 was low (< 5%), although a large proportion of cells harbored viral RNA (around 50%), whilst cell viability was preserved. HLA class I cell surface expression was downregulated in persistently infected cultures, but HLA class I mRNA levels were unchanged in comparison with mock-infected cells. The cytolytic activities of IL-2-activated non-adherent peripheral blood mononuclear cells (PBMCs) and of NK cells were higher towards persistently infected cells than towards mock-infected cells, as assessed by an LDH release assay. Impaired cytolytic activity of IL-2-activated non-adherent PBMCs from patients with T1D towards infected beta cells was observed. In conclusion, pancreatic beta cells persistently infected with CV-B4 can be lysed by NK cells, implying that impaired cytolytic activity of these effector cells may play a role in the persistence of CV-B in the host and thus in the viral pathogenesis of T1D.

Keywords: Enterovirus; HLA class I; LDH assay; Persistence; Type 1 diabetes.

MeSH terms

  • Adult
  • Cell Line
  • Coxsackievirus Infections / complications*
  • Coxsackievirus Infections / immunology
  • Coxsackievirus Infections / virology
  • Diabetes Mellitus, Type 1 / etiology
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / virology*
  • Enterovirus B, Human / immunology*
  • Humans
  • Immunity, Cellular
  • Insulin-Secreting Cells / immunology
  • Insulin-Secreting Cells / virology*
  • Killer Cells, Natural / immunology*
  • Middle Aged