Novel regulation of LAT-mediated T cell signaling by DNA-PKcs 

---

Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B697
Abstract ID: 4615

Presenting Author:
Randall Rainwater , Graduate Student at Univ. of Arkansas for Med. Sci., Arkansas Children's Res. Inst.

Abstract:

T cell response to alloantigen contributes significantly to kidney transplant rejection. Despite conventional therapies, approximately one-third of patients fail treatment, leading to poor long-term graft survival. Identifying targetable proteins that regulate the allogenic T cell response is crucial for developing new therapies to address T cell-mediated rejection (TCMR) effectively. The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) has emerged as a target for T cell regulation, prompting interest in its therapeutic potential. Prior studies inhibiting DNA-PKcs have demonstrated reduced TCMR in a murine skin graft model, decreased T cell activation markers CD69 and CD25, decreased T cell proliferation, and attenuated the CD8+ cytotoxic response. These findings suggest the promise of DNA-PKcs inhibitors as immunotherapy for T cell-mediated disorders. In this study, we aimed to characterize the mechanistic role of DNA-PKcs in T cell signaling, shedding light on its clinical potential. We discovered, for the first time, that DNA-PKcs phosphorylates the integral T cell signaling scaffold protein, the Linker for Activation of T cells (LAT). Blocking DNA-PKcs phosphorylation of LAT hinders LAT scaffold function and blocks cytokine production, without affecting T cell proliferation. These results show the critical role of DNA-PKcs in the antigenic response providing support for future investigations into DNA-PKcs regulation of T cell signaling for the treatment of TCMR.