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 5

βST mice have reduced IL-12p35 expression in islet myeloid cells.

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βST mice have reduced IL-12p35 expression in islet myeloid cells. (A and...
(A and B) Normalized cell count of classical macrophages (CD11b+CD11c–F4/80+Gr1–), hybrid macrophages (CD11b+CD11c+F4/80+Gr1–), cDC1s (CD11b–CD11c+F4/80–Gr1–), and cDC2s (CD11b+CD11c+F4/80–Gr1–) per islet (A) or per pancreatic lymph node (B) from euglycemic 14-week-old NOD βST or littermate mice. (C) Representative flow cytometry histogram of IL-12p35 expression in cDC2s from islets of euglycemic 14-week-old NOD βST and NOD littermate mice, compared with isotype control. (D) Representative flow cytometry histogram of IL-12p35 expression in hybrid macrophages from islets of euglycemic NOD βST and littermate mice, compared with isotype control. Vertical line denotes the positive gate. (E) Quantification of IL-12p35 expression shown in C and D across 7 NOD βST mice, 16 NOD littermate mice, and 5 isotype controls. Error bars represent SD. Mann-Whitney U tests were used to examine statistical differences between groups.