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Processing in the Endoplasmic Reticulum Generates an Epitope on the Insulin A Chain that Stimulates Diabetogenic CD8 T Cell Responses¹

Helen Brosi,^2* Michael Reiser,^2* Tarvo Rajasalu, Andreas Spyrantis,^* Franz Oswald,^* Bernhard Otto Boehm,^* and Reinhold Schirmbeck^3*

*Department of Internal Medicine I, University Hospital of Ulm, Ulm, Germany; and Department of Internal Medicine and Immunology, University of Tartu, Tartu, Estonia

RIP-B7.1 mice express the costimulator molecule B7.1 (CD80) on pancreatic β cells and are a well-established model for studying de novo induction of diabetogenic CD8 T cells. Immunization of RIP-B7.1 mice with preproinsulin (ppins)-encoding plasmid DNA efficiently induces experimental autoimmune diabetes (EAD). EAD is associated with an influx of CD8 T cells specific for the K^b/A_12–21 epitope into the pancreatic islets and the subsequent destruction of β cells. In this study, we used this model to investigate how ppins-derived Ags are expressed and processed to prime diabetogenic, K^b/A_12–21-specific CD8 T cells. Targeting the K^b/A_12–21 epitope, the insulin A chain, or the ppins to the endoplasmic reticulum (ER) (but not to the cytosol and/or nucleus) efficiently elicited K^b/A_12–21-specific CD8 T cell responses. The K^b/A_12–21 epitope represents the COOH terminus of the ppins molecule and, hence, did not require COOH-terminal processing before binding its restriction element in the ER. However, K^b/A_12–21-specific CD8 T cells were also induced by COOH-terminally extended ppins-specific polypeptides expressed in the ER, indicating that the epitope position at the COOH terminus is less important for its diabetogenicity than is targeting the Ag to the ER. The K^b/A_12–21 epitope had a low avidity for K^b molecules. When epitopes of unrelated Ags were coprimed at the same site of Ag delivery, "strong" K^b-restricted (but not D^b-restricted) CD8 T cell responses led to the suppression of K^b/A_12–21-specific CD8 T cell priming and reduced EAD. Thus, direct expression and processing of the "weak" K^b/A_12–21 epitope in the ER favor priming of autoreactive CD8 T cells.

Correspondence: ³ Address correspondence and reprint requests to Dr. Reinhold Schirmbeck, Department of Internal Medicine I, University of Ulm, Albert Einstein Allee 23, D-89081 Ulm, Germany. E-mail address: reinhold.schirmbeck{at}uniklinik-ulm.de

¹ This work was supported by grants from the Center of Excellence Baden-Württemberg "Metabolic Disorders" to B.O.B. and from the Deutsche Forschungsgemeinschaft: SFB 518/A01 and GRK-1041 (to R.S. and B.O.B.), SFB 518/A18 (to F.O.), and DFG SCHI-505/2-4 (to R.S.).

² H.B. and M.R. contributed equally to this work.