Induction of Innate Immune Response through TLR2 and Dectin 1 Prevents Type 1 Diabetes

Abstract

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-β1, IL-2, and TNF-α. 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-selectinhigh T cell frequencies and enhanced suppressor function of CD4+CD25+ T regulatory cells. Further, activation by anti-CD3-Ab induced larger amounts of TGF-β1 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.

Th17 Polarized Cells from Nonobese Diabetic Mice Following Mycobacterial Adjuvant Immunotherapy Delay Type 1 Diabetes

“…It should be noted that we used adjuvants without autoantigens in our protection model. It has been shown that multiple injections of zymosan, three times in the first week and injection in weeks 3, 5, 7, 9, and 11, could prevent diabetes development (37). We just used a single injection of zymosan.…”

C-type lectin receptor-induced NF-κB activation in innate immune and inflammatory responses

“…Further experiments showed that zymozan treatment resulted in a decrease in immune cell infiltrate in b-islets, reduced b-islet destruction, increased naive or regulatory T cell phenotype and enhanced regulatory T suppressor function. 93 TLR-2 and Dectin-1 ligation by zymosan was shown to induce IL-10 and TGF-b expression, but it is unclear if these results are solely due to suppressive cytokine expression. Taken together, these data suggest that CLR targeting may induce immune tolerance through the induction of regulatory T cells, or by enhancing the activity of existing regulatory T cells.…”

Helminth Infection and Type 1 Diabetes

“…Complete Freund's adjuvant [84] Streptococcal OK-432 [85] Klebsiella pneumonia glycoprotein [86] Escherischia coli LPS [86] Zymosan [87] Zymosan [88] CpG DNA [89] CpG DNA [90] Polyinosinic:polycytidylic acid [80] OM-85 (multi-species extract) [91] Pseudomonas aeruginosa OdDHL [92] Legend: LNFPIII -lacto-N-fucopentaose III, BCG -baccilus calmette-guerin, LPS -lipopolysaccharide, OdDHL -N-(3-oxododecanoyl)-L-homoserine lactone.…”