Fig. 2

Main signaling pathways involved in CD19-BBζ T cells and CD19-28ζ T cells. a A high mitochondrial respiratory capacity promotes metabolism and differentiation. 4-1BB domain signaling activates the PI3K pathway and upregulates Bcl-xL and BFL-1 expression. Tonic CAR-derived 4-1BB signaling activates the NF-B pathway and enhances FAS-dependent apoptosis. CD19-BBζ T cells diminish the expression of exhaustion-associated molecules more than CD19-28ζ T cells. b The main signaling pathways involved in CD19-28ζ T cells. CAR T cell inhibition induced by regulatory T cells, IL-10 and TGF-β can be reduced by the incorporation of the CD28 domain. CD19-28ζ T cells exhibit enhanced activation of the transcription factor NF-B and promote cytokine secretion. CD19-28ζ T cells are more likely to result in the development of severe CRS than CD19-BBζ T cells. However, tonic CAR CD3ζ phosphorylation triggered by clustering of the CAR single-chain variable fragment (scFv) leads to more rapid exhaustion