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Triggering a second T cell receptor on diabetogenic T cells can prevent induction of diabetes
G Fossati1, A Cooke, R Q Papafio
1Division of Molecular Immunology, The National Institute for Medical Research, London NW7 1AA, United Kingdom.
Abstract:
In this paper, we test the hypothesis that triggering of a second T cell receptor (TCR) expressed on diabetogenic T cells might initiate the onset of diabetes. A cross between two TCR-transgenic strains, the BDC2.5 strain that carries diabetogenic TCRs and the A18 strain that carries receptors specific for C5, was set up to monitor development of diabetes after activation through the C5 TCR. F1 BDC2. 5 x A18 mice developed diabetes spontaneously beyond 3-4 mo of age. Although their T cells express both TCRs constitutively, the A18 receptor is expressed at extremely low levels. In vitro activation of dual TCR T cells followed by adoptive transfer into neonatal or adult F1 mice resulted in diabetes onset and death within 10 d after transfer. In contrast, in vivo immunization of F1 mice with different forms of C5 antigen not only failed to induce diabetes but protected mice from the spontaneous onset of diabetes. We propose that antigenic stimulation of cells with low levels of TCR produces signals inadequate for full activation, resulting instead in anergy.
Insights
Triggering a second T cell receptor (TCR) on diabetogenic T cells can initiate diabetes. However, low-level TCR stimulation may lead to anergy, protecting against diabetes onset.
Area of Science:
- Immunology
- Endocrinology
- Autoimmunity
Background:
- Type 1 diabetes is an autoimmune disease characterized by the destruction of pancreatic beta cells.
- T cell receptor (TCR) signaling plays a critical role in T cell activation and the development of autoimmune diseases.
- Dual-TCR expressing T cells offer a unique model to study TCR signaling thresholds in autoimmunity.
Purpose of the Study:
- To investigate the hypothesis that triggering a second TCR on diabetogenic T cells initiates diabetes onset.
- To explore the role of TCR signaling strength in dictating T cell activation versus anergy in the context of autoimmune diabetes.
Main Methods:
- Generation of F1 BDC2.5 x A18 mice with dual TCR expression (diabetogenic and C5-specific).
- In vitro activation of dual-TCR T cells followed by adoptive transfer.
- In vivo immunization with C5 antigen to assess its effect on spontaneous diabetes development.
Main Results:
- F1 mice developed spontaneous diabetes, indicating the presence of diabetogenic T cells.
- In vitro activated dual-TCR T cells induced rapid diabetes onset and mortality upon adoptive transfer.
- In vivo C5 antigen immunization protected mice from spontaneous diabetes, suggesting an anergy-inducing mechanism.
Conclusions:
- TCR signaling strength is crucial in determining the outcome of T cell activation in autoimmune diabetes.
- High-level TCR stimulation can trigger diabetes, while low-level stimulation may induce T cell anergy and protection.
- These findings provide insights into the complex regulation of autoimmune responses and potential therapeutic strategies for diabetes.