| Autor: |
Nabavieh, Ali, Chou, Henry, Volokhov, Irina, Lee, James E, Purdy, Lisa E, Elliott, John F, Singh, Bhagirath, Madrenas, Joaquı́n |
| Zdroj: |
Journal of Autoimmunity; February 1998, Vol. 11 Issue: 1 p63-72, 10p |
| Abstrakt: |
Insulin-dependent diabetes mellitus (IDDM) results from chronic, T-cell dependent, autoimmune destruction of the insulin-producing β-cells in the Langerhans’ islets of the pancreas. Non-obese diabetic (NOD) mice spontaneously develop IDDM that resembles human type I diabetes. The susceptibility to diabetes in the NOD strain is a complex polygenic trait that determines a phenotype of immune alterations. The unique MHC class II molecule expressed by NOD mice (I-Ag7) plays a major role in the development of disease. Recently, it has been reported that I-Ag7molecules generate a lower proportion of compact αβheterodimers, compared to other haplotypes. However, it is not clear whether this reflects an intrinsic defect of this molecule to bind peptide stably or is the result of abnormal processing and/or peptide loading into the I-Ag7molecule. Our aim was to develop and characterize a suitable antigen-presenting cell (APC) that expressed I-Ag7in the context of a non-diabetes-prone antigen processing and presentation machinery. Here, we report the generation of a mouse DAP.3 fibroblast cell line (DAP.3Ag7) that constitutively expresses high levels of I-Ag7. Using DAP.3 cells transfected with I-Ag7or I-Ak, we show that the expression of compact dimers in the same cell type is proportionally less for I-Ag7molecules than for I-Akmolecules, implying an intrinsic defect of the I-Ag7molecule as the cause for the low generation of compact dimers. However, DAP.3Ag7cells are able to process and present antigen, as indicated by I-Ag7-dependent IL-2 production by a GAD67-specific NDO T-cell hybridoma after stimulation with GAD and live, but not fixed, DAP.3Ag7cells. The IL-2 response to GAD when presented by DAP.3Ag7was significantly higher than the response to GAD presented by NOD splenocytes. Based on these data, we conclude that the low generations of compact dimers is an intrinsic feature of I-Ag7molecules and not affected by other genes in the NOD background. The DAP.3Ag7cell line should be a valuable tool with which to dissect the role of the I-Ag7molecule in antigen presentation and T-cell activation in NOD mice, which clearly contributes to the development of IDDM. |
| Databáze: |
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