# DNA-PKcs controls the cytotoxic T cell response to cancer and transplant allograft through regulating LAT-dependent signaling

## TL;DR

DNA-PKcs helps T cells fight cancer and prevent transplant rejection by regulating LAT signaling at the immune synapse.

## Contribution

DNA-PKcs is newly identified as a regulator of LAT-dependent T cell signaling and function.

## Key findings

- DNA-PKcs interacts with LAT and localizes to the immune synapse upon T cell activation.
- Inhibiting DNA-PKcs impairs LAT localization and reduces T cell function in tumor control and graft rejection.
- Phosphorylation of LAT serines S224 and S241 by DNA-PKcs affects T cell signaling and cytokine production.

## Abstract

Formation of the immune synapse (IS) following T cell antigen recognition includes recruitment of the linker for activation of T cells (LAT). Once at the IS, LAT tyrosines are phosphorylated, allowing it to serve as a scaffold for the formation of the “signalosome,” a multiprotein complex that drives T cell receptor signaling. Here, we show that upon T cell activation, DNA-dependent protein kinase catalytic subunit (DNA-PKcs) interacts with LAT and localizes to the IS. Inhibition of DNA-PKcs diminishes LAT localization at the IS. We identified two LAT serines phosphorylated by DNA-PKcs, S224 and S241, that impact LAT tyrosine phosphorylation, protein binding, and cytokine production. Using our mouse model designed to delete DNA-PKcs expression in mature CD4+ or CD8+ T cells, we show that loss of DNA-PKcs results in T cells that are unable to control tumor growth or induce allogeneic graft rejection. These data highlight DNA-PKcs as a pivotal protein in T cell function.

Rainwater et al. show that DNA-PKcs plays a role in early T cell activation by regulating signaling through LAT at the immune synapse. By influencing how T cells respond to antigens, DNA-PKcs emerges as a promising therapeutic target, and inhibiting DNA-PKcs may offer a powerful approach to preventing transplant rejection.