ST8Sia6 overexpression protects pancreatic β cells from spontaneous autoimmune diabetes in nonobese diabetic mice
Justin Choe, Paul Belmonte, Sydney Crotts, Thanh Nguyen, David Friedman, Alexi Zastrow, Matthew Rajcula, Brady Hammer, Claire Wilhelm, Michael J. Shapiro, Aleksey Matveyenko, Virginia Smith Shapiro
Justin Choe, Paul Belmonte, Sydney Crotts, Thanh Nguyen, David Friedman, Alexi Zastrow, Matthew Rajcula, Brady Hammer, Claire Wilhelm, Michael J. Shapiro, Aleksey Matveyenko, Virginia Smith Shapiro
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Research Article Autoimmunity Immunology

ST8Sia6 overexpression protects pancreatic β cells from spontaneous autoimmune diabetes in nonobese diabetic mice

Abstract

Type 1 diabetes is characterized by the autoimmune destruction of pancreatic β cells, resulting in permanent loss of glucose homeostasis. Islet transplantation is a promising potential cure that remains hindered by immune rejection. We previously showed that ST8Sia6 expression on tumors reduced immune surveillance and hypothesized that this sialyltransferase could protect β cells from autoimmune destruction. Here, we demonstrate that ectopic expression of ST8Sia6 in β cells of female nonobese diabetic mice (NOD βST) decreased the spontaneous incidence of diabetes by 90% and preserved β cell mass. NOD βST mice had comparable insulitis at 8 weeks of age that did not progress over time compared with littermate controls. β Cell–autoreactive B and T cells were present in NOD βST mice, indicating a peripheral rather than central mechanism of immune tolerance. The islets of NOD βST mice displayed a dampened type 1 immune response and reduced IL-12p35 expression in dendritic cells compared with those of littermate controls. The peripheral protection persisted even after removal of ST8Sia6 expression at 20 weeks of age, indicating that transient expression was sufficient for establishment of tolerance. These results demonstrate that ST8Sia6 protects β cells from immune-mediated attack and rejection, highlighting its therapeutic potential for autoimmune disorders.

Authors

Justin Choe, Paul Belmonte, Sydney Crotts, Thanh Nguyen, David Friedman, Alexi Zastrow, Matthew Rajcula, Brady Hammer, Claire Wilhelm, Michael J. Shapiro, Aleksey Matveyenko, Virginia Smith Shapiro

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Figure 1

Expression of ST8Sia6 in the islets of NOD female mice protects from spontaneous disease.

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Expression of ST8Sia6 in the islets of NOD female mice protects from spo...
(A) Schematic representation of the genetic model. (B) Representative IHC imaging for the myc-tagged ST8Sia6 in pancreas sections from each genetic combination of alleles in female mice. Only βST mice expressing all 3 alleles stain positive for myc-tagged ST8Sia6 in the islets. Scale bars: 100 μm (black) or 50 μm (white). (C) Kaplan-Meier curve for diabetes-free incidence in female NOD βST and NOD littermate mice. n = 50 (NOD βST) or 151 (littermates). Statistical significance was determined by log-rank Mantel-Cox test. (D) Subanalysis by allelic expression of the littermate population from C for diabetes-free incidence. n = 50 (NOD βST), 62 (LNL-tTA), 76 (RIP-Cre), 67 (ST8Sia6), or 15 (no alleles); the sum of littermate subgroups exceeds 151 because some littermates carried 2 alleles and were thus counted in more than one group. Statistical significance was determined by log-rank Mantel-Cox test comparing each littermate group against NOD βST. (E) Assessment of the extent of immune infiltration into the islets of nondiabetic female NOD βST and littermate mice at 8 weeks, 20 weeks, and 300 days of age. Insulitis was scored along a 4-point scale (0, no insulitis; 1, 0%–25% infiltration; 2, 26%–50% infiltration; 3, 51%–75% infiltration; 4, 76%–100% infiltration) from H&E-stained sections. Analysis was performed on 45 islets from 4 βST and 72 islets from 7 littermate mice at 8 weeks; 50 islets from 6 βST and 59 islets from 12 littermate mice at 20 weeks; and 119 islets from 16 βST and 76 islets from 17 littermate mice at 300 days. Distribution of scores is plotted, and statistical analysis was performed using a χ2 test on islet scores for indicated comparisons.