Notch2-expressing CD4⁺ T cells attain immunoregulatory functions during autoimmune inflammation

Autoantigen-specific CD4⁺ T cells are central to the development of autoimmune diseases, while the expansion of regulatory T (Treg) cells expressing Forkhead box protein 3 (Foxp3) is essential for mitigating these conditions. In this study, we identified CD4⁺Notch2⁺Foxp3^lo T cells in the spinal cords of mice with experimental autoimmune encephalomyelitis (EAE), dextran sodium sulfate-induced colitis model mice, and patients with ulcerative colitis as immune regulatory cells. These cells exhibited a nonproliferative, dysfunctional phenotype and demonstrated immune regulatory functions, including suppressive activity against activated CD4⁺ T cells and marked Treg cell expansion activity. Our data revealed that Notch2 deletion in Foxp3-expressing cells diminishes the ability of this population to reverse the clinical symptoms of EAE. Collectively, these findings suggest that Notch2 expression in dysfunctional CD4⁺ T cells plays a crucial role in immune regulation.