Role of DNA-LL37 complexes in the activation of plasmacytoid dendritic cells and monocytes in subjects with type 1 diabetes

• Published in: Scientific reports Vol. 10; no. 1; p. 8896
• Main Authors: Badal, Darshan, Dayal, Devi, Singh, Gunjan, Sachdeva, Naresh
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2020; Nature Publishing Group
• Subjects: 13/21; 13/31; 14/19; 14/34; 631/250/38; 692/163/2743/137/1418; 692/308/3187; Adolescent; Antigen Presentation; Antigens, CD - metabolism; Antigens, Differentiation, T-Lymphocyte - metabolism; Antimicrobial Cationic Peptides - metabolism; Antimicrobial peptides; Apoptosis; Beta cells; Case-Control Studies; CD4 antigen; CD69 antigen; CD80 antigen; CD86 antigen; Cell activation; Cell culture; Cells, Cultured; Coculture Techniques; Dendritic cells; Dendritic Cells - cytology; Dendritic Cells - immunology; Deoxyribonucleic acid; Diabetes; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - metabolism; DNA; DNA - metabolism; Female; Histocompatibility antigen HLA; Humanities and Social Sciences; Humans; Inflammation; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - metabolism; Interferon; Interferon-alpha - metabolism; Lectins, C-Type - metabolism; Lymphocytes T; Male; Monocytes; Monocytes - cytology; Monocytes - metabolism; multidisciplinary; Pancreas; Phenotypes; Receptors, Transferrin - metabolism; Science; Science (multidisciplinary); Tryptophan 2,3-dioxygenase; Young Adult; α-Interferon
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-65851-y

Initiation of type 1 diabetes (T1D) is marked by the infiltration of plasmacytoid dendritic cells (pDCs) and monocytes in pancreatic islets. Dying beta cells release self-DNA, which forms complexes with antimicrobial peptide, LL37, and its delayed clearance can activate pDCs and monocytes. Here, we studied the phenotypic effects of DNA-LL37 complexes on pDCs and monocytes in 55 recently diagnosed T1D and 25 healthy control (HC) subjects. Following in vitro stimulation with DNA-LL37 complexes, T1D group demonstrated higher frequency and mean fluorescence intensity (MFI) of pDCs expressing IFN-α. Similarly, the monocytes in T1D group showed an increase in MFI of IFN-α. Post-stimulation, an increase in the antigen presentation and co-stimulatory ability of pDCs and monocytes was observed in T1D group, as indicated by higher expression of HLA-DR, CD80 and CD86. Upon co-culture, the stimulated monocytes and pDCs, particularly in the T1D group were able to further activate autologous CD4 + T cells, with increase in expression of CD69 and CD71. Finally, in a transwell assay, the stimulated pDCs and monocytes induced an increase in apoptosis of 1.1B4 beta cells. Additionally, we observed reduced expression of indoleamine 2,3-dioxygenase 1 (IDO1) in pDCs and monocytes of T1D subjects. Our results suggest that DNA-LL37 complexes activate pDCs and monocytes towards a proinflammatory phenotype during pathogenesis of T1D.