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Published on: May 6, 2013
Toll-like receptor 7 stimulation promotes autoimmune diabetes in the NOD mouse
A S Lee1, M Ghoreishi, W K Cheng
1Department of Dermatology and Skin Science, Child and Family Research Institute, The University of British Columbia, 950 West 28th Avenue, Vancouver, BC, Canada V5Z 4H4.
Aims/Hypothesis:
The role of Toll-like receptor 7 (TLR7), a sensor of viral and self RNA, in promoting autoimmune diabetes remains unclear. Our goal was to determine the effect of TLR7 stimulation on the priming and activation of diabetogenic CD8(+) T cells.
Methods:
We explored the effects of CL097 (TLR7/8 agonist) and immunoregulatory sequence 661 (IRS661, TLR7 inhibitor) on bone marrow-derived dendritic cells (BMDCs), diabetogenic CD8(+) T cell function and autoimmune diabetes onset in NOD and 8.3 NOD T cell receptor transgenic mice (8.3 NOD mice).
Results:
TLR7 stimulation of NOD BMDCs increased activation and production of proinflammatory cytokines. In vivo administration of CL097 activated T cells and dendritic cells and increased levels of proinflammatory cytokines and type 1/2 IFNs in NOD mice. In vivo antigen-specific cytotoxicity studies revealed enhanced cytotoxicity against islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP, an islet autoantigen) peptide pulsed targets in NOD mice treated with CL097 plus CD40 agonist. This combination treatment accelerated the onset of autoimmune diabetes in 8.3 NOD mice. Likewise, topical treatment of NOD mice with a TLR7 agonist accelerated diabetes onset. Spontaneous disease in 8.3 NOD mice and accelerated disease in CL097+CD40 agonist-treated 8.3 NOD mice were delayed by IRS661 treatment, which is associated with inhibition of the endogenous upregulation of IFN-α levels within the pancreatic lymph nodes.
Conclusions/Interpretation:
TLR7 stimulation accelerates the spontaneous onset of autoimmune diabetes in 8.3 NOD and NOD mice. Conversely, TLR7 inhibition prevents the early events associated with diabetogenesis.
Insights
Toll-like receptor 7 (TLR7) stimulation accelerates autoimmune diabetes by activating immune cells. Inhibiting TLR7 delays diabetes onset, suggesting TLR7 is a key target for preventing this autoimmune condition.
Area of Science:
- Immunology
- Autoimmune Diseases
- T-cell Biology
Background:
- Toll-like receptor 7 (TLR7) senses viral and self RNA, but its role in autoimmune diabetes is unclear.
- Understanding TLR7's impact on diabetogenic CD8(+) T cells is crucial for autoimmune diabetes research.
Purpose of the Study:
- To determine the effect of TLR7 stimulation on priming and activation of diabetogenic CD8(+) T cells.
- To investigate the role of TLR7 in the development of autoimmune diabetes.
Main Methods:
- Utilized CL097 (TLR7/8 agonist) and IRS661 (TLR7 inhibitor) in NOD and 8.3 NOD mice models.
- Assessed bone marrow-derived dendritic cells (BMDCs), CD8(+) T cell function, and autoimmune diabetes onset.
- Conducted in vivo antigen-specific cytotoxicity and cytokine level analyses.
Main Results:
- TLR7 stimulation enhanced NOD BMDC activation and pro-inflammatory cytokine production.
- In vivo TLR7 agonist treatment increased T cell and dendritic cell activation, pro-inflammatory cytokines, and type 1/2 IFNs.
- TLR7 stimulation accelerated autoimmune diabetes onset in mice, while TLR7 inhibition delayed it.
Conclusions:
- TLR7 stimulation accelerates autoimmune diabetes in NOD and 8.3 NOD mouse models.
- TLR7 inhibition effectively prevents early diabetogenesis events.
- Targeting TLR7 may offer a therapeutic strategy for autoimmune diabetes.
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