{"doi":"10.1101/2022.06.23.497236","title":"Inhibition of DNA-PKcs impairs the activation and cytotoxicity of CD4 <sup>+</sup> helper and CD8 <sup>+</sup> effector T cells","abstract":"Abstract Modulation of T cell activity is an effective strategy for the treatment of autoimmune diseases, immune-related disorders and cancer. This highlights a critical need for continued investigation of proteins that regulate T cell function. The kinase DNA -dependent p rotein k inase c atalytic s ubunit (DNA-PKcs) is emerging as a potent regulator of the immune system spurring interest in its use as a therapeutic target for immune-related diseases. In murine models of autoimmune disease including asthma and rheumatoid arthritis, treatment with small molecule DNA-PKcs inhibitors, which are in clinical trials for cancer therapy, decreased disease severity. Additionally, DNA-PKcs inhibitors reduced T cell-mediated graft rejection and extended graft survival in a murine allogenic skin graft rejection model. These in vivo studies suggest the therapeutic use of DNA-PKcs inhibitors for autoimmune and T cell-mediated disorders. In this study, we sought to further characterize the effects of DNA-PKcs inhibitors on T cells to better understand their clinical potential. We determined that pharmacological inhibition of DNA-PKcs abrogated activation of murine and human CD4 + and CD8 + T cells as evident by reduced expression of the activation markers CD69 and CD25. Furthermore, inhibition of DNA-PKcs impeded metabolic pathways and proliferation of anti-CD3/CD28 activated CD4 + and CD8 + T cells as well as peptide-stimulated OTI-CD8 + T cells. This reduced the ability of OTI-CD8 + T cells to kill cancer cells and the expression of IFN γ and the cytotoxic genes eomes, perforin and granzyme B. These results suggest a novel role for DNA-PKcs in early T cell activation. Furthermore, our data support the therapeutic potential of DNA-PKcs inhibitors on diseases of immune dysregulation.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":309491,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9549,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1004792,"name":"Lauren Appell","orcid":null,"position":1,"is_corresponding":false},{"id":719527,"name":"Lyle Burdine","orcid":"0000-0002-5892-2281","position":2,"is_corresponding":false},{"id":543056,"name":"Lora J. Rogers","orcid":null,"position":3,"is_corresponding":false},{"id":699389,"name":"Lauren C. Morehead","orcid":"0000-0002-2883-4299","position":4,"is_corresponding":false},{"id":82101,"name":"Melanie Barker","orcid":null,"position":5,"is_corresponding":false},{"id":719526,"name":"Zachary J. Waldrip","orcid":"0000-0002-4210-8832","position":6,"is_corresponding":false},{"id":489796,"name":"Brian Koss","orcid":"0000-0003-0155-4809","position":7,"is_corresponding":false},{"id":720112,"name":"Marie Burdine","orcid":null,"position":8,"is_corresponding":false},{"id":532240,"name":"Ana Clara P. Azevedo‐Pouly","orcid":"0000-0001-8308-9271","position":0,"is_corresponding":true}],"reference_count":38,"raw_metadata":null,"created_at":"2026-07-19T00:33:11.579763Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}