Deficiency of Nuclear Factor-κB c-Rel Accelerates the Development of Autoimmune Diabetes in NOD Mice

Area of Science:

• Immunology
• Molecular Biology
• Endocrinology

Background:

• Nuclear factor-kappa B (NF-κB) protein c-Rel is implicated in autoimmunity.
• c-Rel-deficient mice resist chemically induced autoimmune diabetes.
• The role of c-Rel in spontaneous autoimmune diabetes is unclear.

Purpose of the Study:

• To investigate the role of c-Rel in the development of spontaneous autoimmune diabetes in Non-Obese Diabetic (NOD) mice.
• To elucidate the mechanisms underlying c-Rel's function in autoimmune diabetes pathogenesis.

Main Methods:

• Generation of c-Rel-deficient NOD mice.
• Analysis of T cell function (IL-2, IFN-γ, GM-CSF expression) via T-cell receptor induction.
• Assessment of insulitis and hyperglycemia.
• Evaluation of regulatory T (Treg) cell numbers and function.
• Treg cell supplementation experiments.

Main Results:

• c-Rel deficiency in NOD mice led to decreased T cell cytokine production (IL-2, IFN-γ, GM-CSF).
• c-Rel deficiency significantly accelerated insulitis and hyperglycemia, hallmarks of autoimmune diabetes.
• A substantial reduction in regulatory T (Treg) cell numbers was observed in c-Rel-deficient NOD mice.
• Supplementation with c-Rel-competent Treg cells reversed the accelerated diabetes development.

Conclusions:

• c-Rel-dependent regulatory T (Treg) cell function is crucial for suppressing early-onset autoimmune diabetes in NOD mice.
• This study reveals a novel protective role for c-Rel in spontaneous autoimmune diabetes, contrasting its role in other autoimmune diseases.
• A distinct mechanism for c-Rel in spontaneous versus chemically induced diabetes is identified.