title: Distinct activation of primary human BDCA1(+) dendritic cells upon interaction with stressed or infected β cells.
abstract: Derailment of immune responses can lead to autoimmune type 1 diabetes, and this can be accelerated or even induced by local stress caused by inflammation or infection. Dendritic cells (DCs) shape both innate and adaptive immune responses. Here, we report on the responses of naturally occurring human myeloid BDCA1(+) DCs towards differentially stressed pancreatic β cells. Our data show that BDCA1(+) DCs in human pancreas-draining lymph node (pdLN) suspensions and blood-derived BDCA1(+) DCs both effectively engulf β cells, thus mimicking physiological conditions. Upon uptake of enterovirus-infected, but not mock-infected cells, BDCA1(+) DCs induced interferon (IFN)-α/β responses, co-stimulatory molecules and proinflammatory cytokines and chemokines. Notably, induction of stress in β cells by ultraviolet irradiation, culture in serum-free medium or cytokine-induced stress did not provoke strong DC activation, despite efficient phagocytosis. DC activation correlated with the amount of virus used to infect β cells and required RNA within virally infected cells. DCs encountering enterovirus-infected β cells, but not those incubated with mock-infected or stressed β cells, suppressed T helper type 2 (Th2) cytokines and variably induced IFN-γ in allogeneic mixed lymphocyte reaction (MLR). Thus, stressed β cells have little effect on human BDCA1(+) DC activation and function, while enterovirus-infected β cells impact these cells significantly, which could help to explain their role in development of autoimmune diabetes in individuals at risk.
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: B M
authors.initials: BM
authors.lastname: Schulte
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: E D
authors.initials: ED
authors.lastname: Kers-Rebel
authors.affiliation: Department of Pediatrics, Diabetes Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Bottino
authors.affiliation: Department of Pediatrics, Diabetes Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Piganelli
authors.affiliation: Department of Medical Microbiology, Radboud University Medical Center, Nijmegen.
authors.forename: J M D
authors.initials: JM
authors.lastname: Galama
authors.affiliation: Department of Nephrology, Leiden University Medical Center, Leiden.
authors.forename: M A
authors.initials: MA
authors.lastname: Engelse
authors.affiliation: Department of Nephrology, Leiden University Medical Center, Leiden.|Department of Endocrinology, Leiden University Medical Center, Leiden.|Hubrecht Institute, Utrecht, the Netherlands.
authors.forename: E J P
authors.initials: EJ
authors.lastname: de Koning
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: G J
authors.initials: GJ
authors.lastname: Adema
mesh_terms: D000818:Animals; D018949:Antigens, CD1 / Q000235:genetics / Q000276:immunology*; D002450:Cell Communication / Q000276:immunology*; D018920:Coculture Techniques; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D029822:Enterovirus B, Human / Q000276:immunology* / Q000472:pathogenicity; D015870:Gene Expression; D006023:Glycoproteins / Q000235:genetics / Q000276:immunology*; D054884:Host-Pathogen Interactions; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology / Q000821:virology; D007371:Interferon-gamma / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D051379:Mice; D010587:Phagocytosis / Q000187:drug effects; D011070:Poly I-C / Q000494:pharmacology; D061251:Primary Cell Culture; D015398:Signal Transduction; D013312:Stress, Physiological; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014466:Ultraviolet Rays
chemical_list: D018949:Antigens, CD1; C437944:CD1C protein, human; D016895:Culture Media, Serum-Free; D006023:Glycoproteins; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D011070:Poly I-C
keywords: BDCA1+ myeloid DC; DC maturation; enterovirus; human; islets of Langerhans; β cells