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Published on: April 21, 2015
Role of CD28 in fatal autoimmune disorder in scurfy mice
Nagendra Singh1, Phillip R Chandler, Yoichi Seki
1Immunotherapy Center, Medical College of Georgia, Augusta, USA.
Abstract:
Scurfy mice develop CD4 T-cell-mediated lymphoproliferative disease leading to death within 4 weeks of age. The scurfy mutation causes loss of function of the foxp3 gene (foxp3(sf)), which is essential for development and maintenance of naturally occurring regulatory CD4 T cells (nTregs). In humans, mutations of the foxp3 gene cause immune dysregulation, polyendocrinopathy, enteropathy, and X-linked syndrome (IPEX). In most patients with IPEX and also in scurfy mice, T cells show hyperreactivity and levels of Th1- and Th2-associated cytokines are substantially elevated. We report that removal of CD28 expression rescued scurfy mice from early death. Longer-term surviving CD28-deficient scurfy mice still had lymphoproliferative disorder, but their CD4 T cells showed decreased interferon-gamma and no sign of interleukin-4 or interleukin-10 hyperproduction. Furthermore, injection of CTLA4-Ig to block CD28-B7 interactions substantially improved the survival of scurfy mice by blocking effector T-cell differentiation. These data support the hypothesis that CD28-B7 interactions play a critical role in the etiology of lethal autoimmune disease in scurfy mice by stimulating the differentiation of antigen-activated naive T cells into effector T cells.
Insights
Blocking CD28 signaling prevents fatal autoimmune disease in scurfy mice. This research highlights CD28-B7 interactions
Area of Science:
- Immunology
- Genetics
- Molecular Biology
Background:
- Scurfy mice exhibit fatal CD4 T-cell lymphoproliferative disease due to foxp3 gene mutations, impacting regulatory T cells.
- This mirrors human IPEX syndrome, characterized by immune dysregulation and elevated Th1/Th2 cytokines.
- T-cell hyperreactivity is a hallmark of both scurfy mice and IPEX patients.
Purpose of the Study:
- To investigate the role of CD28-B7 interactions in the pathogenesis of scurfy mice.
- To determine if modulating CD28 signaling can rescue scurfy mice from early mortality.
Main Methods:
- Genetic deletion of CD28 in scurfy mice.
- Administration of CTLA4-Ig to block CD28-B7 interactions.
- Analysis of T-cell populations, cytokine profiles, and survival rates.
Main Results:
- CD28 deficiency rescued scurfy mice from early death, improving survival.
- CD28-deficient scurfy mice showed reduced interferon-gamma and normalized interleukin-4/interleukin-10 levels.
- CTLA4-Ig treatment significantly improved survival by inhibiting effector T-cell differentiation.
Conclusions:
- CD28-B7 interactions are critical drivers of lethal autoimmune disease in scurfy mice.
- Blocking CD28 signaling prevents effector T-cell differentiation and ameliorates disease severity.
- Targeting CD28-B7 pathways offers a potential therapeutic strategy for related autoimmune conditions.
