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Cell Mol Life Sci. 2019 Jun 6. doi: 10.1007/s00018-019-03168-4. [Epub ahead of print]

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

Author information

1
Université de Lille, Faculté de Médecine, CHU de Lille, Laboratoire de Virologie EA3610, 59000, Lille, France.
2
Université d'Abomey-Calavi, Faculté des Sciences et Techniques, Institut des Sciences Biomédicales Appliquées (ISBA), Laboratoire de Biologie et Physiologie Cellulaires, 01 BP 526, Cotonou, Benin.
3
Université de Lille, INSERM U995, LIRIC-Lille, CHU de Lille, Institut d'Immunologie, 59000, Lille, France.
4
Polyclinique, Service de Médecine Programmée, 62000, Henin-Beaumont, France.
5
Université de Lille, Faculté de Médecine, CHU de Lille, Laboratoire de Virologie EA3610, 59000, Lille, France. didier.hober@chru-lille.fr.
6
Laboratoire de Virologie EA3610, Centre Paul Boulanger, Hôpital A Calmette, CHRU, Boulevard du Professeur Jules Leclercq, 59037, Lille Cedex, France. didier.hober@chru-lille.fr.

Abstract

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

PMID:
31172216
DOI:
10.1007/s00018-019-03168-4

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