The microbial product lipopolysaccharide confers diabetogenic potential onthe T cell repertoire of BDC2.5/NOD mice: Implications for the etiology ofautoimmune diabetes

Both genetic predisposition and environmental factors participate in the et iology of Type-1 diabetes. To test the role of the microbial product lipopo lysaccharide (LPS) as an environmental trigger of autoimmune diabetes, we e mployed transgenic (tg) BDC2.5/NOD mice that bear an islet-specific CD4(+) T cell repertoire (>95%), but do not develop the spontaneous diabetes that typifies the NOD (nonobese diabetic) strain. LPS administration provoked di abetes in BDC2.5/NOD mice by their 16th week of age, However, LPS administr ation in NOD mice did not accelerate their diabetes. This finding indicates that the frequency of islet-specific T cells influences LPS-mediated diabe tes, Furthermore, in vitro LPS-cultured splenocytes from BDC2.5/NOD and BDC 2.5-mu MT (B-cell-deficient) mice effectively transferred diabetes into imm unodeficient NOD-scid/scid mice but not immunosufficient NOD mice. Therefor e, B lymphocytes are not required for LPS-provoked autoimmune diabetes. Flo w cytometric analysis then revealed that LPS-stimulation in vitro induced t he expression of an IL-2 receptor (CD25) on CD4 T cells; this indicates tha t the activation of islet-specific T cells is a prerequisite to eliciting d iabetes in this situation. Overall, these results point to microbial LPS as an etiopathogenic agent of autoimmune diabetes. (C) 2000 Academic Press.