CTLA-4 Facilitates DNA Damage-Induced Apoptosis by Interacting With PP2A.

Qiongyu Yan,Xi Ling,Dongjie Zhang,Bin Zhang,Jiping Huo,Shenghui Mei,Zhigang Zhao,Hua Yang,Bin Zhu

doi:10.3389/fcell.2022.728771

Abstract

Cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) plays a pivotal role in regulating immune responses. It accumulates in intracellular compartments, translocates to the cell surface, and is rapidly internalized. However, the cytoplasmic function of CTLA-4 remains largely unknown. Here, we describe the role of CTLA-4 as an immunomodulator in the DNA damage response to genotoxic stress. Using isogenic models of murine T cells with either sufficient or deficient CTLA-4 expression and performing a variety of assays, including cell apoptosis, cell cycle, comet, western blotting, co-immunoprecipitation, and immunofluorescence staining analyses, we show that CTLA-4 activates ataxia–telangiectasia mutated (ATM) by binding to the ATM inhibitor protein phosphatase 2A into the cytoplasm of T cells following transient treatment with zeocin, exacerbating the DNA damage response and inducing apoptosis. These findings provide new insights into how T cells maintain their immune function under high-stress conditions, which is clinically important for patients with tumors undergoing immunotherapy combined with chemoradiotherapy.

Highlights

T lymphocytes (T cells) execute various functions in defense against pathogens and tumors and interact with other cells involved in immune responses
Cytotoxic T-lymphocyte–associated protein 4 (CTLA-4)–deficient mice die at 18–28 days due to the generation of self-reactive T cells (Chambers et al, 2001)
We investigated the role of CTLA-4 in the genotoxic stress response induced by zeocin treatment by comparing freshly isolated CD4+ T cells from B7-1/ B7-2−/− and B7-1/B7-2/CTLA-4−/− mice

Summary

Introduction

T lymphocytes (T cells) execute various functions in defense against pathogens and tumors and interact with other cells involved in immune responses. T cells have a life span of several decades and the highest proliferative potential, and T-cell DNA is damaged by diverse endogenous and environmental stress factors (Opzoomer et al, 2019). These cells have developed a complex DNA damage response (DDR) to promote the maintenance of genome integrity (Bouwman and Jonkers, 2012). Double strand breaks (DSBs) are the most harmful DNA lesions in cells. These “dirty” DSBs that remain “uncleaned” may cause gene mutations, genomic instability, and carcinogenesis (Ciccia and Elledge, 2010; Hanahan and Weinberg, 2011). The identification and development of mechanisms that induce T-cell apoptosis or increase susceptibility to genomic stress are useful for maintaining the health of organisms

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