Induction of innate immune response through TLR2 and dectin 1 prevents type 1 diabetes.
Studies have suggested a correlation between the decline in infectious diseases and increase in the incidence of type 1 diabetes (T1D) in developed countries. Pathogens influence the disease outcome through innate immune receptors such as TLRs. Here we report the effect of ligation of TLR2 and dectin 1 on APCs and the influence of innate immune response induced through these receptors on T1D. Exposure of APCs of NOD mice to zymosan, a fungal cell wall component that interacts with TLR2 and dectin 1, resulted in the release of significant amounts of IL-10, TGF-beta1, IL-2, and TNF-alpha. Treatment of pre- and early hyperglycemic mice with zymosan resulted in suppression of insulitis, leading to a significant delay in hyperglycemia. T cells from zymosan-treated mice showed reduced ability to induce diabetes in NOD-Scid mice compared with control T cells. Zymosan treatment induced suppression of T1D was associated with an increase in the L-selectin(high) T cell frequencies and enhanced suppressor function of CD4(+)CD25(+) T regulatory cells. Further, activation by anti-CD3-Ab induced larger amounts of TGF-beta1 and/or IL-10 production by CD4(+)CD25(+) and CD4(+)CD25(-) T cells from zymosan-treated mice. These results show that innate immune response through TLR2 and dectin 1 results in suppressor cytokine production by APCs and promotes the regulatory function of T cells. Our study demonstrates the possible involvement of signaling through innate immune receptors such as TLR2 and dectin 1 in reduced T1D incidence under the conditions of low hygiene, and the potential of targeting them for treating T1D.
Karumuthil-Melethil
Subha
S
Department of Surgery, College of Medicine, University of Illinois, Chicago, IL 60612, USA.
Perez
Nicolas
N
Li
Ruobing
R
Vasu
Chenthamarakshan
C
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D003433:Crosses, Genetic; D016207:Cytokines / Q000096:biosynthesis / Q000502:physiology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control*; D005260:Female; D006943:Hyperglycemia / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D006946:Hyperinsulinism / Q000235:genetics / Q000517:prevention & control; D007113:Immunity, Innate; D037181:Lectins, C-Type; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009419:Nerve Tissue Proteins / Q000502:physiology*; D011236:Prediabetic State / Q000235:genetics / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000502:physiology*; D015054:Zymosan / Q000008:administration & dosage / Q000502:physiology; D000099181:Dectin-1
D016207:Cytokines; D037181:Lectins, C-Type; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D051195:Toll-Like Receptor 2; D015054:Zymosan; D000099181:Dectin-1; C493486:Tlr2 protein, mouse