# DNA-PKcs Regulation of LAT-Mediated Early TCR Signaling in CD4+ and CD8+ T Cells

> **NIH NIH R21** · ARKANSAS CHILDREN'S HOSPITAL RES INST · 2023 · $231,000

## Abstract

Project Summary
 Identification of small molecule protein targets that modulate T cell activity continues to be a therapeutic
goal when treating patients with cancer, autoimmune diseases, and allogeneic organ rejection. To that end,
our laboratory has determined that the druggable kinase DNA dependent-protein kinase catalytic subunit
(DNA-PKcs) is required for CD4+ and CD8+ T cell function. We observe robust DNA-PKcs activation following
T cell stimulation, and once activated, DNA-PKcs is necessary to initiate several key immunogenic transcriptional
programs including those driven by the transcription factors NFAT, NF𝜅B, and EGR1. Importantly, both chemical
and genetic inhibition of DNA-PKcs significantly disrupts T cell activation, metabolism, cytokine production and
the ability of cytotoxic T cells to kill target cells. To gain insight into the molecular mechanisms by which DNA-
PKcs regulates T cell activity, we performed a phospho-proteomic screen of T cells treated with a small molecule
DNA-PKcs inhibitor. Data from this screen and our follow-up studies confirm the TCR signaling protein Linker for
Activation of T cells (LAT) as a significant phosphorylation target of DNA-PKcs. In this proposal, we will utilize
novel inducible transgenic mouse models designed to “knockout” DNA-PKcs expression specifically in mature
CD4+ or CD8+ lymphocytes to evaluate the relevance of DNA-PKcs phosphorylation of LAT to T cell function
and its impact on T cell response to antigen stimulation. In Aim 1, we will characterize the interaction between
LAT and DNA-PKcs through in vitro studies using DNA-PKcs-deficient CD4+ or CD8+ T cells and CRISPR-
generated LAT phosphomutants. Aim 2 will focus on determining how loss of DNA-PKcs either before or after
T cell activation impacts CD4+ and CD8+ T cell response to antigen in vivo using the OVA-specific TCR transgenic
OTII and OTI mouse models. Completion of these aims will provide new insights into a completely
uncharacterized signaling mechanism that significantly impacts CD4+ and CD8+ T cell-mediated immunity with
considerable implications for novel therapy approaches.

## Key facts

- **NIH application ID:** 10741023
- **Project number:** 1R21AI173759-01A1
- **Recipient organization:** ARKANSAS CHILDREN'S HOSPITAL RES INST
- **Principal Investigator:** Marie Schluterman Burdine
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $231,000
- **Award type:** 1
- **Project period:** 2023-08-05 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10741023

## Citation

> US National Institutes of Health, RePORTER application 10741023, DNA-PKcs Regulation of LAT-Mediated Early TCR Signaling in CD4+ and CD8+ T Cells (1R21AI173759-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10741023. Licensed CC0.

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