TLR2- and Dectin 1-associated innate immune response modulates T-cell response to pancreatic β-cell antigen and prevents type 1 diabetes.
The progression of autoimmune diseases is dictated by deviations in the fine balance between proinflammatory versus regulatory responses, and pathogen recognition receptors (PRRs) play a key role in maintaining this balance. Previously, we have reported that ligation of Toll-like receptor 2 (TLR2) and Dectin 1 on antigen-presenting cells by zymosan results in a regulatory immune response that prevents type 1 diabetes (T1D). Here, we show that TLR2 and Dectin 1 engagement by zymosan promotes regulatory T-cell (Treg) responses against the pancreatic β-cell-specific antigen (Ag). Unlike the TLR4 ligand, bacterial lipopolysaccharide, which induced proinflammatory cytokines and pathogenic T cells, zymosan induced a mixture of pro- and anti-inflammatory factors and Tregs, both in vitro and in vivo. Ag-specific T cells that are activated using zymosan-exposed dendritic cells (DCs) expressed Foxp3 and produced large amounts of IL-10, TGF-β1, and IL-17. NOD mice that received β-cell-Ag-loaded, zymosan-exposed DCs showed delayed hyperglycemia. Injection of NOD mice at the prediabetic age and early hyperglycemic stage with β-cell-Ag, along with zymosan, results in a superior protection of the NOD mice from diabetes as compared with mice that received zymosan alone. This therapeutic effect was associated with increased frequencies of IL-10-, IL-17-, IL-4-, and Foxp3-positive T cells, especially in the pancreatic lymph nodes. These results show that zymosan can be used as an immune regulatory adjuvant for modulating the T-cell response to pancreatic β-cell-Ag and reversing early-stage hyperglycemia in T1D.
Department of Surgery, University of Illinois at Chicago, Chicago, IL.
Subha
S
Karumuthil-Melethil
Department of Microbiology and Immunology, College of Medicine, Medical University of South Carolina, Charleston, SC.
M Hanief
MH
Sofi
Department of Surgery, College of Medicine, Medical University of South Carolina, Charleston, SC.
Radhika
R
Gudi
Department of Microbiology and Immunology, College of Medicine, Medical University of South Carolina, Charleston, SC.
Benjamin M
BM
Johnson
Department of Surgery, University of Illinois at Chicago, Chicago, IL.
Nicolas
N
Perez
Department of Microbiology and Immunology, College of Medicine, Medical University of South Carolina, Charleston, SC Department of Surgery, College of Medicine, Medical University of South Carolina, Charleston, SC vasu@musc.edu.
Chenthamarakshan
C
Vasu
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D007113:Immunity, Innate / Q000276:immunology*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000276:immunology*; D037181:Lectins, C-Type / Q000378:metabolism*; D051379:Mice; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D015054:Zymosan / Q000494:pharmacology; D000099181:Dectin-1
D016207:Cytokines; D037181:Lectins, C-Type; D051195:Toll-Like Receptor 2; D015054:Zymosan; D000099181:Dectin-1; C493486:Tlr2 protein, mouse