High-affinity chimeric antigen receptor signaling induces an inflammatory program in human regulatory T cells.

IF 4.6 2区医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL

Molecular Therapy-Methods & Clinical Development Pub Date : 2024-11-18 eCollection Date: 2024-12-12 DOI:10.1016/j.omtm.2024.101385

Russell W Cochrane, Rob A Robino, Bryan Granger, Eva Allen, Silvia Vaena, Martin J Romeo, Aguirre A de Cubas, Stefano Berto, Leonardo M R Ferreira

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引用次数: 0

Abstract

Regulatory T cells (Tregs) are promising cellular therapies to induce immune tolerance in organ transplantation and autoimmune disease. The success of chimeric antigen receptor (CAR) T cell therapy for cancer has sparked interest in using CARs to generate antigen-specific Tregs. Here, we compared CAR with endogenous T cell receptor (TCR)/CD28 activation in human Tregs. Strikingly, CAR Tregs displayed increased cytotoxicity and diminished suppression of antigen-presenting cells and effector T (Teff) cells compared with TCR/CD28-activated Tregs. RNA sequencing revealed that CAR Tregs activate Teff cell gene programs. Indeed, CAR Tregs secreted high levels of inflammatory cytokines, with a subset of FOXP3⁺ CAR Tregs uniquely acquiring CD40L surface expression and producing IFN-γ. Interestingly, decreasing CAR antigen affinity reduced Teff cell gene expression and inflammatory cytokine production by CAR Tregs. Our findings showcase the impact of engineered receptor activation on Treg biology and support tailoring CAR constructs to Tregs for maximal therapeutic efficacy.

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高亲和力嵌合抗原受体信号诱导人类调节性 T 细胞的炎症程序。

调节性 T 细胞（Tregs）是在器官移植和自身免疫性疾病中诱导免疫耐受的一种很有前景的细胞疗法。嵌合抗原受体（CAR）T细胞疗法治疗癌症的成功引发了人们对使用CAR产生抗原特异性Tregs的兴趣。在这里，我们比较了CAR与内源性T细胞受体（TCR）/CD28在人类Tregs中的激活情况。引人注目的是，与TCR/CD28激活的Tregs相比，CAR Tregs显示出更强的细胞毒性，对抗原递呈细胞和效应T（Teff）细胞的抑制作用减弱。RNA 测序显示 CAR Tregs 激活了 Teff 细胞基因程序。事实上，CAR Tregs 能分泌高水平的炎症细胞因子，其中一个 FOXP3+ CAR Tregs 亚群能独特地获得 CD40L 表面表达并产生 IFN-γ。有趣的是，降低 CAR 抗原的亲和力会减少 Teff 细胞基因的表达和 CAR Tregs 产生的炎性细胞因子。我们的研究结果展示了工程受体活化对 Treg 生物学的影响，并支持为 Tregs 定制 CAR 构建物以获得最大疗效。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Therapy-Methods & Clinical Development Biochemistry, Genetics and Molecular Biology-Molecular Biology

CiteScore

9.90

自引率

4.30%

发文量

163

审稿时长

12 weeks

期刊介绍： The aim of Molecular Therapy—Methods & Clinical Development is to build upon the success of Molecular Therapy in publishing important peer-reviewed methods and procedures, as well as translational advances in the broad array of fields under the molecular therapy umbrella. Topics of particular interest within the journal''s scope include: Gene vector engineering and production, Methods for targeted genome editing and engineering, Methods and technology development for cell reprogramming and directed differentiation of pluripotent cells, Methods for gene and cell vector delivery, Development of biomaterials and nanoparticles for applications in gene and cell therapy and regenerative medicine, Analysis of gene and cell vector biodistribution and tracking, Pharmacology/toxicology studies of new and next-generation vectors, Methods for cell isolation, engineering, culture, expansion, and transplantation, Cell processing, storage, and banking for therapeutic application, Preclinical and QC/QA assay development, Translational and clinical scale-up and Good Manufacturing procedures and process development, Clinical protocol development, Computational and bioinformatic methods for analysis, modeling, or visualization of biological data, Negotiating the regulatory approval process and obtaining such approval for clinical trials.