Toll-like receptor 2 senses beta-cell death and contributes to the initiation of autoimmune diabetes.
Although it is established that defective clearance and, hence, increased accumulation of apoptotic cells can lead to autoimmunity, the mechanism by which this occurs remains elusive. Here, we observed that apoptotic cells undergoing secondary necrosis but not intact apoptotic cells provoked substantial immune responses, which were mediated through the toll-like receptor 2 (TLR2) pathway. The development of autoimmune diabetes was markedly inhibited in Tlr2(-/-) mice but not in Tlr4(-/-) mice, showing that TLR2 plays an important role in the initiation of the disease. Apoptotic beta-cell injury could stimulate the priming of diabetogenic T cells through a TLR2-dependent, but TLR4-independent, activation of antigen-presenting cells. These findings suggest that beta-cell death and its sensing via TLR2 may be an initial event for the stimulation of antigen-presenting cells and development of autoimmune diabetes.
Kim
Hun Sik
HS
Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
Han
Myoung Sook
MS
Chung
Kun Wook
KW
Kim
Sunshin
S
Kim
Eunshil
E
Kim
Myoung Joo
MJ
Jang
Eunkyeong
E
Lee
Hyun Ah
HA
Youn
Jeehee
J
Akira
Shizuo
S
Lee
Myung-Shik
MS
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015551:Autoimmunity / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016923:Cell Death; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D050417:Insulin-Secreting Cells / Q000473:pathology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000502:physiology
D016328:NF-kappa B; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4