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Induction of Innate Immune Response through TLR2 and Dectin 1 Prevents Type 1 Diabetes¹

Department of Surgery, College of Medicine, University of Illinois, Chicago, IL 60612

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-. 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-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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by the Department of Surgery, University of Illinois at Chicago; National Institutes of Health Grants R21A1059745 and R21AI069848; and Juvenile Diabetes Research Foundation awards 1-2005-27 and 32-2008-343.

² Address correspondence and reprint requests to Dr. Chenthamarakshan Vasu, Department of Surgery, University of Illinois at Chicago, 909 South Wolcott, College of Medicine Research Building, 7113, M/C790, Chicago, IL 60612. E-mail address: chenta{at}uic.edu

³ Abbreviations used in this paper: T1D, type 1 diabetes; DC, dendritic cell; Treg, regulatory T cell; Foxp3, foxhead box p3 transcription factor; LP, lipoprotein/lipopeptide; CD62L, L-selectin; BM, bone marrow; BMDC, BM-derived DC; TR, Texas Red; PnLN, pancreatic lymph node; MHC II, MHC class II.