Here, we show an association between Notch signaling and a dysfunctional phenotype of CD4+ T cells − similar to exhaustion and characterized by a nonproliferative state and expression of PD−1, Tim3, and Lag3 − in mouse models of MS (i.e., mice with EAE) and IBD (i.e., mice with dextran sodium sulfate (DSS)−induced colitis). This evidence concerns the gene CD4 and inflammatory bowel disease.