Oral probiotic promotes indoleamine 2,3-dioxygenase- and TGF-β–Producing plasmacytoid dendritic cells to initiate protection against type 1 diabetes

• Published in: Immunology letters 2021-11, Vol.239, p.12-19
• Main Authors: Nelson, Andrew S., Akgul, Ali, Maddaloni, Massimo, Bhagyaraj, Ella, Hoffman, Carol, Pascual, David W.
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Antigens, Bacterial - genetics; Antigens, Bacterial - immunology; Antigens, Bacterial - metabolism; Blood Glucose - analysis; CD4-Positive T-Lymphocytes; Cells, Cultured; Coculture Techniques; Dendritic Cells - immunology; Dendritic Cells - metabolism; Diabetes Mellitus, Type 1 - diagnosis; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - prevention & control; Disease Models, Animal; Female; Fimbriae Proteins - genetics; Fimbriae Proteins - immunology; Fimbriae Proteins - metabolism; Humans; IDO; Indoleamine-Pyrrole 2,3,-Dioxygenase - metabolism; Lactococcus lactis - genetics; Lactococcus lactis - immunology; Lactococcus lactis - metabolism; Lymph Nodes - cytology; Mice; Mice, Transgenic; Plasmacytoid dendritic cells; Primary Cell Culture; Probiotic; Probiotics - administration & dosage; Spleen - cytology; Tolerance; Transforming Growth Factor beta - metabolism; Type 1 diabetes
• ISSN: 0165-2478; 1879-0542
• DOI: 10.1016/j.imlet.2021.07.009

•Infection with LL-CFA/I promotes IDO and TGF-β production from plasmacytoid DCs.•Plasmacytoid DCs in the pancreatic lymph nodes gain regulatory function shortly after LL-CFA/I treatment.•LL-CFA/I infected DCs promote IL-10 production from t cells and restrain TNF-α and IFN-γ. Colonization factor antigen I (CFA/I) fimbria, an adhesin from enterotoxigenic Escherichia coli, confers protection in murine autoimmune models for type 1 diabetes (T1D), multiple sclerosis, and rheumatoid arthritis. Although CFA/I fimbriae's initial mode of action is in a bystander or in an antigen (Ag)-independent fashion, protection is ultimately dependent upon the induction and/or activation of auto-Ag-specific regulatory T cells (Tregs). However, little is known about how protection transitions from bystander suppression to Ag-specific Tregs. Since dendritic cells (DCs) play an integral role in fate decisions for T cells becoming inflammatory or tolerogenic, the described study tests the hypothesis that Lactococcus lactis expressing CFA/I (LL-CFA/I) stimulates DCs to establish a regulatory microenvironment. To this end, bone marrow-derived dendritic cells (BMDCs) were infected in vitro with LL-CFA/I. Results revealed increased production of IL-10, TGF-β, and indoleamine 2,3-deoxygenase (IDO). Although co-culture of LL-CFA/I infected BMDCs with naïve T cells did not promote Foxp3 expression, TNF-α and IFN-γ production was suppressed. NOD mice orally dosed with LL-CFA/I showed an increase in regulatory plasmacytoid DCs (pDCs) expressing IDO and TGF-β in pancreatic lymph nodes (PaLNs) and spleen three days post-treatment. However, Tregs did not appear in the mucosal inductive sites until much later. These findings show that LL-CFA/I influences specific DC populations to establish tolerance.