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Updated: Apr 22, 2026
Accelerated Type 1 Diabetes Induction in Mice by Adoptive Transfer of Diabetogenic CD4+ T Cells
Published on: May 6, 2013
Polymorphism in the innate immune receptor SIRPα controls CD47 binding and autoimmunity in the nonobese diabetic
Andrea Sut Ling Wong1, Steven Mortin-Toth2, Michael Sung2
1Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S1A8, Canada; Program in Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario M5G1X8, Canada;
Abstract:
The signal regulatory protein (SIRP) locus encodes a family of paired receptors that mediate both activating and inhibitory signals and is associated with type 1 diabetes (T1D) risk. The NOD mouse model recapitulates multiple features of human T1D and enables mechanistic analysis of the impact of genetic variations on disease. In this study, we identify Sirpa encoding an inhibitory receptor on myeloid cells as a gene in the insulin-dependent diabetes locus 13.2 (Idd13.2) that drives islet inflammation and T1D. Compared to T1D-resistant strains, the NOD variant of SIRPα displayed greater binding to its ligand CD47, as well as enhanced T cell proliferation and diabetogenic potency. Myeloid cell-restricted expression of a Sirpa transgene accelerated disease in a dose-dependent manner and displayed genetic and functional interaction with the Idd5 locus to potentiate insulitis progression. Our study demonstrates that variations in both SIRPα sequence and expression level modulate T1D immunopathogenesis. Thus, we identify Sirpa as a T1D risk gene and provide insight into the complex mechanisms by which disease-associated variants act in concert to drive defined stages in disease progression.
Insights
Signal regulatory protein alpha (SIRPα) drives type 1 diabetes (T1D) by promoting islet inflammation. Genetic variations in SIRPα enhance its binding to CD47, increasing T cell proliferation and disease severity in NOD mice.
Area of Science:
- Immunology
- Genetics
- Endocrinology
Background:
- The signal regulatory protein (SIRP) locus is linked to type 1 diabetes (T1D) risk.
- The NOD mouse model is a key tool for studying T1D pathogenesis.
Purpose of the Study:
- Identify genes within the insulin-dependent diabetes locus 13.2 (Idd13.2) contributing to T1D.
- Investigate the role of SIRPα in T1D development and progression.
Main Methods:
- Utilized the NOD mouse model to analyze genetic variations in SIRPα.
- Assessed SIRPα binding to CD47, T cell proliferation, and disease acceleration.
- Examined interactions between Sirpa and the Idd5 locus.
Main Results:
- Identified Sirpa as a T1D risk gene within Idd13.2, driving islet inflammation.
- The NOD variant of SIRPα showed increased CD47 binding, enhanced T cell proliferation, and greater diabetogenic potency.
- Myeloid cell-specific Sirpa expression accelerated T1D in a dose-dependent manner and interacted with Idd5.
Conclusions:
- SIRPα sequence and expression levels significantly modulate T1D immunopathogenesis.
- Sirpa acts as a T1D risk gene, contributing to disease progression through complex genetic interactions.
