RRC ID 67502
著者 Oda T, Nakamura R, Kasamatsu T, Gotoh N, Okuda K, Saitoh T, Handa H, Murakami H, Yamashita T.
タイトル DNA-double strand breaks enhance the expression of major histocompatibility complex class II through the ATM-NF-κΒ-IRF1-CIITA pathway.
ジャーナル Cancer Gene Ther
Abstract Major histocompatibility complex class II (MHC II) is important for the adaptive immune response because MHC II presents processed antigens to a cluster of differentiation 4 (CD4)-positive T-cells. Conventional doses of chemotherapeutic agents induce tumor cell death by causing DNA double-strand breaks (DSBs). However, cellular responses caused by sub-lethal doses of chemotherapeutic agents are poorly understood. In this study, using low doses of chemotherapeutic agents, we showed that DSBs enhanced the expression of MHC II on cells that originate from antigen-presenting cells (APCs). These agents induced the MHC class II transactivator (CIITA), the master regulator of MHC II, and interferon regulatory factor 1 (IRF1), a transcription factor for CIITA. Short hairpin RNA against IRF1 suppressed chemotherapeutic agent-induced CIITA expression, whereas exogenous expression of IRF1 induced CIITA. Inhibition of ataxia-telangiectasia mutated (ATM), a DSB-activated kinase, suppressed induction of IRF1, CIITA, and MHC II. Similar results were observed by inhibiting NF-κB, a downstream target of ATM. These results suggest that DSBs induce MHC II activity via the ATM-NF-κB-IRF1-CIITA pathway in cells that intrinsically present antigens. Additionally, chemotherapeutic agents induced T-cell regulatory molecules. Our findings suggest that chemotherapeutic agents enhance the antigen presentation activity of APCs for T-cell activation.
巻・号 29(2)
ページ 225-240
公開日 2022-2-1
DOI 10.1038/s41417-021-00302-y
PII 10.1038/s41417-021-00302-y
PMID 33619341
MeSH Ataxia Telangiectasia* / genetics Ataxia Telangiectasia Mutated Proteins / genetics Ataxia Telangiectasia Mutated Proteins / metabolism DNA DNA Breaks, Double-Stranded* Histocompatibility Antigens Class II / genetics Histocompatibility Antigens Class II / metabolism Humans Interferon Regulatory Factor-1 / genetics Interferon Regulatory Factor-1 / metabolism Interferon-gamma / genetics Major Histocompatibility Complex Nuclear Proteins Promoter Regions, Genetic Trans-Activators
IF 4.534
リソース情報
ヒト・動物細胞 V79(RCB0008)