Rewired signaling network in T cells expressing the chimeric antigen receptor (CAR)

The chimeric antigen receptor (CAR) directs T cells to target and kill specific cancer cells. Despite the success ofCART therapy in clinics, the intracellular signaling pathways that lead toCART cell activation remain unclear. UsingCD19CARas a model, we report that, similar to the endogenous T cell receptor (TCR), antigen engagement triggers the formation ofCARmicroclusters that transduce downstream signaling. However,CARmicroclusters do not coalesce into a stable central supramolecular activation cluster (cSMAC). Moreover,LAT, an essential scaffold protein forTCRsignaling, is not required for microcluster formation, immunological synapse formation, nor actin remodeling followingCARactivation. However,CART cells still requireLATfor an optimal production of the cytokineIL-2. Together, these data show thatCART cells can bypassLATfor a subset of downstream signaling outputs, thus revealing a rewired signaling pathway as compared to native T cells.