Abstract
Non-obese diabetic (NOD) mice are well-established models of independently developing spontaneous autoimmune diseases, Sjögren’s syndrome (SS) and type 1 diabetes (T1D). The key determining factor for T1D is the strong association with particular MHCII molecule and recognition by diabetogenic T cell receptor (TCR) of an insulin peptide presented in the context of I-Ag7 molecule. For SS the association with MHCII polymorphism is weaker and TCR diversity involved in the onset of the autoimmune phase of SS remains poorly understood. To compare the impact of TCR diversity reduction on the development of both diseases we generated two lines of TCR transgenic NOD mice. One line expresses transgenic TCRβ chain originated from a pathogenically irrelevant TCR, and the second line additionally expresses transgenic TCRαmini locus. Analysis of TCR sequences on NOD background reveals lower TCR diversity on Treg cells not only in the thymus, but also in the periphery. This reduction in diversity does not affect conventional CD4+ T cells, as compared to the TCRmini repertoire on B6 background. Interestingly, neither transgenic TCRβ nor TCRmini mice develop diabetes, which we show is due to lack of insulin B:9–23 specific T cells in the periphery. Conversely SS develops in both lines, with full glandular infiltration, production of autoantibodies and hyposalivation. It shows that SS development is not as sensitive to limited availability of TCR specificities as T1D, which suggests wider range of possible TCR/peptide/MHC interactions driving autoimmunity in SS.
Highlights
Non-obese diabetic (NOD) mice serve as well-established models of independently developing autoimmune diseases, Type 1 Diabetes (T1D) and Sjogren’s syndrome (SS) [1,2]
The TCRb transgenic chain originated from I-Ab restricted T cell receptor (TCR) specific to Ep63 K peptide an analog of Ea 52–68 peptide in which the residue at position 63(I) was substituted with lysine [40]
In this study we investigated the impact of the reduction of TCR diversity on the development of two autoimmune diseases in NOD mice; T1D and SS
Summary
NOD mice serve as well-established models of independently developing autoimmune diseases, Type 1 Diabetes (T1D) and Sjogren’s syndrome (SS) [1,2]. Autoimmunity in NOD mice is attributed to several different events occurring in the thymus and in the periphery. Studies in these mice showed a defect in negative selection [7], perturbed ab/cd lineage decision leading to a shift in selection niches [8], reduced relative diversity of thymic Treg cells [9], peripheral hyper-responsiveness of effector CD4+ T cells [10], multiple binding registers of insulin B:9–23 peptide resulting in poor negative selection in the thymus [11,12], or peripheral posttranslational modification of self-peptides/neo-antigens [13]. In large-scale association study of SS in humans, HLA was found to have the strongest linkage to the disease [17]
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