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Sci. STKE, 28 August 2007
Vol. 2007, Issue 401, p. tw309
[DOI: 10.1126/stke.4012007tw309]


Autoimmunity Toll-like Receptor 2 and Type 1 Diabetes

John F. Foley

Science’s STKE, AAAS, Washington, DC 20005, USA

Clearance of apoptotic cells by phagocytosis helps prevent the leakage of cellular contents that may stimulate inflammation or autoimmunity. Nonobese diabetic (NOD) mice develop type I diabetes (T1D) because of the impaired phagocytosis of apoptotic pancreatic beta cells by macrophages; however the mechanism involved is unclear. Kim et al. (see commentary by Filippi and von Herrath) examined the responses of mouse macrophages [which enter the pancreas at the onset of T1D and later act as antigen-presenting cells (APCs) for T cells] to exposure to MIN6N8 insulinoma cells in various stages of radiation-induced cell death. Whereas incubation of macrophages with apoptotic MIN6N8 cells did not stimulate production of the pro-inflammatory cytokine tumor necrosis factor-{alpha} (TNF-{alpha}), as measured by enzyme-linked immunosorbant assay (ELISA), secondary necrotic (SN) cells resulted in substantial TNF-{alpha} production. SN cells are late-stage, intact apoptotic cells that can be distinguished from apoptotic cells by flow cytometry on the basis of cell size and staining for markers of cell death and are characteristic of apoptotic cells that escaped phagocytosis. Gel-shift experiments showed that incubation of macrophages with SN MIN6N8 cells resulted in activation of the transcription factor nuclear factor-{kappa}B (NF-{kappa}B). Exposure of macrophages from Tlr2–/– mice to SN cells resulted in a lower amount of TNF-{alpha} production than did exposure of wild-type macrophages to the cells. Tlr2–/– mice were more resistant to T1D induced by pharmacological killing of beta cells than were wild-type mice (as assessed by histological analysis of islets). Coculture and adoptive transfer experiments in mice showed that TLR2 was necessary for the maturation of APCs and the subsequent activation and proliferation of T cells that mediate T1D. These results link the accumulation of apoptotic cells with TLR2-dependent initiation of autoimmunity, raising the possibility of targeting TLR2 signaling in apoptosis-related diseases and autoimmune disorders.

H. S. Kim, M. S. Han, K. W. Chung, S. Kim, E. Kim, M. J. Kim, E. Jang, H. A. Lee, J. Youn, S. Akira, M.-S. Lee, Toll-like receptor 2 senses beta-cell death and contributes to the initiation of autoimmune diabetes. Immunity 27, 321-333 (2007). [PubMed]

C. M. Filippi, M. G. von Herrath, Islet beta-cell death: Fuel to sustain autoimmunity? Immunity 27, 183-185 (2007). [Online Journal]

Citation: J. F. Foley, Toll-like Receptor 2 and Type 1 Diabetes. Sci. STKE 2007, tw309 (2007).

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