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.