Jul 10, 2020

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

The EMBO Journal
Rui DongXiaolei Su

Abstract

The chimeric antigen receptor (CAR) directs T cells to target and kill specific cancer cells. Despite the success of CAR T therapy in clinics, the intracellular signaling pathways that lead to CAR T cell activation remain unclear. Using CD19 CAR as a model, we report that, similar to the endogenous T cell receptor (TCR), antigen engagement triggers the formation of CAR microclusters that transduce downstream signaling. However, CAR microclusters do not coalesce into a stable central supramolecular activation cluster (cSMAC). Moreover, LAT, an essential scaffold protein for TCR signaling, is not required for microcluster formation, immunological synapse formation, nor actin remodeling following CAR activation. However, CAR T cells still require LAT for an optimal production of the cytokine IL-2. Together, these data show that CAR T cells can bypass LAT for a subset of downstream signaling outputs, thus revealing a rewired signaling pathway as compared to native T cells.

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Mentioned in this Paper

Cytokine
T-Lymphocyte
Downstream
T-Cell Activation
Scaffold protein
Clinic
LAT
Immunological Synapse Formation
Signal Transduction Downstream of Smoothened
Tumor Cells, Malignant

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