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

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.

• Authors: Rui Dong, Kendra A Libby, Franziska Blaeschke, Walker Fuchs, Alexander Marson, Ronald D Vale, Xiaolei Su
• Journal: The EMBO journal (EMBO J) Vol. 39 Issue 16 Pg. e104730 (08 17 2020) ISSN: 1460-2075 [Electronic] England
• PMID: 32643825 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors.

Chemical References

• IL2 protein, human
• Interleukin-2
• Receptors, Chimeric Antigen

Topics

• HEK293 Cells
• Humans
• Immunological Synapses (genetics, immunology)
• Interleukin-2 (genetics, immunology)
• Jurkat Cells
• Receptors, Chimeric Antigen (genetics, immunology)
• Signal Transduction (genetics, immunology)
• T-Lymphocytes (immunology)