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Updated: Jul 8, 2026
Bioluminescent Monitoring of Graft Survival in an Adoptive Transfer Model of Autoimmune Diabetes in Mice
Published on: November 18, 2022
Targeting of pancreatic glia in type 1 diabetes
Hubert Tsui1, Yin Chan, Lan Tang
1The Hospital for Sick Children, 555 University Ave., 10th Floor Elm Wing, Rm. 10126, Toronto, Ontario, M5G 1X8, Canada.
Objective:
Type 1 diabetes reflects autoimmune destruction of beta-cells and peri-islet Schwann cells (pSCs), but the mechanisms of pSC death and the T-cell epitopes involved remain unclear.
Research Design And Methods:
Primary pSC cultures were generated and used as targets in cytotoxic T-lymphocyte (CTL) assays in NOD mice. Cognate interaction between pSC and CD8(+) T-cells was assessed by transgenic restoration of beta2-microglobulin (beta2m) to pSC in NOD.beta2m(-/-) congenics. I-A(g7) and K(d) epitopes in the pSC antigen glial fibrillary acidic protein (GFAP) were identified by peptide mapping or algorithms, respectively, and the latter tested by immunotherapy.
Results:
pSC cultures did not express major histocompatibility complex (MHC) class II and were lysed by ex vivo CTLs from diabetic NOD mice. In vivo, restoration of MHC class I in GFAP-beta2m transgenics significantly accelerated adoptively transferred diabetes. Target epitopes in the pSC autoantigen GFAP were mapped to residues 79-87 and 253-261 for K(d) and 96-110, 116-130, and 216-230 for I-A(g7). These peptides were recognized spontaneously in NOD spleens as early as 2.5 weeks of age, with proliferative responses peaking around weaning and detectable lifelong. Several were also recognized by T-cells from new-onset type 1 diabetic patients. NOD mouse immunotherapy at 8 weeks with the CD8(+) T-cell epitope, GFAP 79-87 but not 253-261, significantly inhibited type 1 diabetes and was associated with reduced gamma-interferon production to whole protein GFAP.
Conclusions:
Collectively, these findings elucidate a role for pSC-specific CD8(+) T-cells in islet inflammation and type 1 diabetes pathogenesis, further supporting neuronal involvement in beta-cell demise.
Insights
Peri-islet Schwann cells (pSCs) are destroyed in type 1 diabetes by CD8(+) T-cells targeting GFAP epitopes. Immunotherapy with a specific GFAP epitope inhibited diabetes in NOD mice.
Area of Science:
- Immunology
- Endocrinology
- Neuroscience
Background:
- Type 1 diabetes involves autoimmune destruction of pancreatic beta-cells and peri-islet Schwann cells (pSCs).
- Mechanisms of pSC death and specific T-cell epitopes driving this process remain largely unknown.
- Understanding these mechanisms is crucial for developing targeted therapies for type 1 diabetes.
Purpose of the Study:
- To investigate the role of pSCs in type 1 diabetes pathogenesis.
- To identify T-cell epitopes within the pSC autoantigen glial fibrillary acidic protein (GFAP).
- To evaluate the therapeutic potential of targeting these epitopes in a mouse model of type 1 diabetes.
Main Methods:
- Generation of primary pSC cultures from NOD mice for cytotoxic T-lymphocyte (CTL) assays.
- Assessment of pSC and CD8(+) T-cell interaction using transgenic NOD mice with restored beta2-microglobulin (beta2m) expression in pSCs.
- Identification and characterization of GFAP T-cell epitopes presented by I-A(g7) and K(d) molecules.
- Immunotherapy in NOD mice using identified GFAP epitopes.
Main Results:
- pSCs were lysed by ex vivo CTLs from diabetic NOD mice, and MHC class I restoration accelerated diabetes.
- Specific GFAP epitopes (K(d): 79-87, 253-261; I-A(g7): 96-110, 116-130, 216-230) were identified and recognized by T-cells from young NOD mice and new-onset diabetic patients.
- Immunotherapy with the CD8(+) T-cell epitope GFAP 79-87 significantly inhibited type 1 diabetes in NOD mice, reducing interferon-gamma production.
Conclusions:
- pSC-specific CD8(+) T-cells play a significant role in islet inflammation and type 1 diabetes pathogenesis.
- These findings highlight the involvement of neuronal components in beta-cell destruction.
- Targeting pSC-specific T-cell epitopes represents a potential therapeutic strategy for type 1 diabetes.
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