Mechanistically, increased toxic potential could be related to the fact that CD28 endodomain provides accelerated expansion and a stronger intracellular signal than 4-1BB, which in turn renders CD28-costimulated CAR-T cells less sensitive to antigen density.35 51–53 Therefore, our data imply that the use of 4-1BB, and presumably similarly acting co-stimulatory domains, in CD4 CAR-T cells could be beneficial to diminish CRS severity. Here, CD4 is linked to congenital rubella syndrome.