Type 1 (T1D) and type 2 (T2D) diabetes share pathophysiological
characteristics, yet mechanistic links have remained elusive. T1D results from
autoimmune destruction of pancreatic beta cells, whereas beta cell failure inT2D
is delayed and progressive. Here we find a new genetic component of diabetes
susceptibility in T1D non-obese diabetic (NOD) mice, identifying
immune-independent beta cell fragility. Genetic variation in
Xrcc4 and Glis3 alters the response of NOD
beta cells to unfolded protein stress, enhancing the apoptotic and senescent
fates. The same transcriptional relationships were observed in human islets,
demonstrating the role of beta cell fragility in genetic predisposition to
diabetes.
Regulatory T cells appear to show great potential for use in cellular therapy. In particular, CD4 À CD8 À (double negative (DN)) T cells, which compose 1-3% of the total number of T lymphocytes, exhibit prominent antigen-specific immune tolerance properties and confer immune tolerance in models of allografts and xenografts. We have recently shown that autoimmunediabetes-prone mice carry fewer DN T cells and that this phenotype contributes to autoimmune-prone diabetes susceptibility, suggesting that increasing DN T-cell number in autoimmune-prone individuals may be of therapeutic interest. To achieve this goal, we must first determine whether the remaining DN T cells in autoimmune-prone mice are functional. In addition, we must identify the parameters that regulate the numbers of DN T cells. Herein, we evaluate the immunoregulatory properties of DN T cells in the autoimmune-prone non-obese diabetic (NOD) genetic background. Using 3A9 TCR transgenic mice, we show that DN T cells from both diabetes-resistant B10.Br and genetically autoimmune-prone NOD.H2 k mice show an equivalent immunoregulatory potential on a per cell basis. However, upon stimulation, there is a 10-fold increase in the number of 3A9 TCR transgenic DN T cells that produce interleukin10 (IL-10) from NOD.H2 k mice in comparison with B10.Br mice. We further showed that IL-10 facilitates DN T-cell apoptosis and thus may regulate the number of DN T cells. Taken together, our results show that, although reduced in number, DN T cells from mice carrying an autoimmune-prone genetic background exhibit a potent cytotoxic potential and that DN T-cell expansion is regulated, at least in part, by IL-10.
Autoimmune diseases result from a break in immune tolerance. Various mechanisms of peripheral tolerance can protect against autoimmunity, including immunoregulatory CD4−CD8− double-negative (DN) T cells. Indeed, we have previously shown that diabetes-prone mouse strains exhibit a low proportion of DN T cells relative to that of diabetes-resistant mice, and that a single autologous transfer of DN T cells can impede autoimmune diabetes development, at least in the 3A9 TCR transgenic setting. In this study, we aim to understand the genetic basis for the difference in DN T cell proportion between diabetes-resistant and diabetes-prone mice. We thus perform an unbiased linkage analysis in 3A9 TCR F2 (NOD.H2k × B10.BR) mice and reveal that a locus on chromosome 9, which coincides with Idd2, is linked to the proportion of DN T cells in the lymph nodes. We generate two NOD.H2k.B10-Chr9 congenic mouse strains and validate the role of this genetic interval in defining the proportion of DN T cells. Moreover, we find that the increased proportion of DN T cells in lymphoid organs is associated with a decrease in both diabetes incidence and serum IgG Ab levels. Together, the data suggest that Idd2 is linked to DN T cell proportion and that a physiological increase in DN T cell number may be sufficient to confer resistance to autoimmune diabetes. Altogether, these findings could help identify new candidate genes for the development of therapeutic avenues aimed at modulating DN T cell number for the prevention of autoimmune diseases.
NOD.H2k and NOD.H2h4 mice carry the MHC class II molecule I-Ak associated with susceptibility to experimentally-induced thyroiditis. Dietary iodine enhanced spontaneous thyroid autoimmunity, well known in NOD.H2h4 mice, has not been investigated in NOD.H2k mice. We compared NOD.H2h4 and NOD.H2k strains for thyroiditis and autoantibodies to thyroglobulin (TgAb) and thyroid peroxidase (TPOAb) without or with dietary sodium iodide (NaI) for up to 32 weeks. TgAb levels were significantly higher in NOD.H2h4 than NOD.H2k mice on NaI and TPOAb developed in NOD.H2h4 but not NOD.H2k mice. DNA exome analysis revealed, in addition to the differences in the chromosome (Chr) 17 MHC regions, that NOD.H2k and particularly NOD.H2h4 mice have substantial non-MHC parental DNA. KEGG pathway-analysis highlighted thyroid autoimmunity and immune-response genes on Chr 17 but not on Chr 7 and 15 parental B10.A4R DNA. Studies of parental strains provided no evidence for non-MHC gene contributions. The exon 10 thyroglobulin haplotype, associated with experimentally-induced thyroiditis, is absent in NOD.H2h4 and NOD.H2k mice and is not a marker for spontaneous murine thyroid autoimmunity. In conclusion, the absence of I-E is a likely explanation for the difference between NOD.H2h4 and NOD.H2k mice in TgAb levels and, as in humans, autoantibody spreading to TPO.
On-chip refractive index cytometry (RIC) achieves enhanced discrimination of cells by simultaneously probing the refractive index and whole-cell deformability.
Immunoregulatory T cells have been identified as key modulators of peripheral tolerance and participate in preventing autoimmune diseases. CD4(-)CD8(-) (double negative, DN) T cells compose one of these immunoregulatory T-cell subsets, where the injection of DN T cells confers protection from autoimmune diabetes progression. Interestingly, genetic loci defining the function and number of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) coincide with at least some autoimmune disease susceptibility loci. Herein, we investigate the impact of major insulin-dependent diabetes (Idd) loci in defining the number of DN T cells. We demonstrate that although Idd3, Idd5 and Idd9 loci do not regulate DN T-cell number, NOD mice congenic for diabetes resistance alleles at the Idd13 locus show a partial restoration in DN T-cell number. Moreover, competitive and non-competitive bone marrow chimera experiments reveal that DN T-cell number is defined by a bone marrow-intrinsic, but DN T-cell-extrinsic, factor. This suggests that non-autonomous candidate genes define DN T-cell number in secondary lymphoid organs. Together, our results show that the regulation of DN T-cell number in NOD mice is at least partially conferred by alleles at the Idd13 locus.
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