The microbial product lipopolysaccharide confers diabetogenic potential on the T cell repertoire of BDC2.5/NOD mice: implications for the etiology of autoimmune diabetes.
Both genetic predisposition and environmental factors participate in the etiology of Type-1 diabetes. To test the role of the microbial product lipopolysaccharide (LPS) as an environmental trigger of autoimmune diabetes, we employed 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 diabetes in BDC2.5/NOD mice by their 16th week of age. However, LPS administration in NOD mice did not accelerate their diabetes. This finding indicates that the frequency of islet-specific T cells influences LPS-mediated diabetes. Furthermore, in vitro LPS-cultured splenocytes from BDC2. 5/NOD and BDC2.5-microMT (B-cell-deficient) mice effectively transferred diabetes into immunodeficient NOD-scid/scid mice but not immunosufficient NOD mice. Therefore, B lymphocytes are not required for LPS-provoked autoimmune diabetes. Flow cytometric analysis then revealed that LPS-stimulation in vitro induced the expression of an IL-2 receptor (CD25) on CD4 T cells; this indicates that the activation of islet-specific T cells is a prerequisite to eliciting diabetes in this situation. Overall, these results point to microbial LPS as an etiopathogenic agent of autoimmune diabetes.
Balasa
B
B
Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.
Van Gunst
K
K
Sarvetnick
N
N
D019264:Adoptive Transfer; D000818:Animals; D001327:Autoimmune Diseases / Q000209:etiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology*; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology / Q000276:immunology*; D004926:Escherichia coli / Q000737:chemistry; D015994:Incidence; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008213:Lymphocyte Activation; D051379:Mice; D016688:Mice, Inbred NOD / Q000276:immunology*; D008822:Mice, Transgenic; D012720:Severity of Illness Index; D013154:Spleen / Q000166:cytology
D008070:Lipopolysaccharides