CD4+ and CD8+ cytotoxic T lymphocytes may induce mesenchymal cell apoptosis in IgG4-related disease.,Journal of Allergy and Clinical Immunology

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CD4+ and CD8+ cytotoxic T lymphocytes may induce mesenchymal cell apoptosis in IgG4-related disease.
Journal of Allergy and Clinical Immunology ( IF 14.2 ) Pub Date : 2020-05-30 , DOI: 10.1016/j.jaci.2020.05.022
Cory A Perugino ₁ , Naoki Kaneko ₂ , Takashi Maehara ₂ , Hamid Mattoo ₃ , Jesper Kers ₄ , Hugues Allard-Chamard ₅ , Vinay S Mahajan ₆ , Hang Liu ₇ , Emanuel Della-Torre ₈ , Samuel J H Murphy ₉ , Musie Ghebremichael ₉ , Zachary S Wallace ₁₀ , Marcy B Bolster ₁₀ , Liam M Harvey ₁₀ , Geetha Mylvaganam ₉ , Yesim Tuncay ₉ , Lloyd Liang ₁₁ , Sydney B Montesi ₁₁ , Xiuwei Zhang ₁₂ , Akira Tinju ₁₃ , Keita Mochizuki ₁₃ , Ryusuke Munemura ₁₃ , Mizuki Sakamoto ₁₃ , Masafumi Moriyama ₁₃ , Seiji Nakamura ₁₃ , Nir Yosef ₁₂ , John H Stone ₁₀ , Shiv Pillai ₉

Affiliation

Ragon Institute of MGH, MIT, and Harvard, Cambridge, Mass; Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Boston, Mass.
Ragon Institute of MGH, MIT, and Harvard, Cambridge, Mass; Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan.
Ragon Institute of MGH, MIT, and Harvard, Cambridge, Mass; Immunology and Inflammation Therapeutic Area, Sanofi, Cambridge, Mass.
Ragon Institute of MGH, MIT, and Harvard, Cambridge, Mass; Amsterdam UMC, University of Amsterdam, Amsterdam Infection & Immunity Institute (AI&II), Amsterdam Cardiovascular Sciences (ACS), Amsterdam, The Netherlands; Van't Hoff Institute for Molecular Sciences (HIMS), University of Amsterdam, Amsterdam, The Netherlands.
Ragon Institute of MGH, MIT, and Harvard, Cambridge, Mass; Division of Rheumatology, Faculté de médecine et des sciences de la santé de l' Université de Sherbrooke et Centre de Recherche Clinique Étienne-Le Bel, Sherbrooke Québec, Canada.
Ragon Institute of MGH, MIT, and Harvard, Cambridge, Mass; Department of Pathology, Brigham and Women's Hospital, Boston, Mass.
Ragon Institute of MGH, MIT, and Harvard, Cambridge, Mass; Department of Rheumatology and Immunology, First Hospital of China Medical University, Shenyang, China.
Ragon Institute of MGH, MIT, and Harvard, Cambridge, Mass; Unit of Immunology, Rheumatology, Allergy, and Rare Diseases (UnIRAR), IRCCS San Raffaele Scientific Institute, Milan, Italy.
Ragon Institute of MGH, MIT, and Harvard, Cambridge, Mass.
Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Boston, Mass.
Division of Pulmonary & Critical Care Medicine, Massachusetts General Hospital, Boston, Mass.
University of California, Berkeley, Calif.
Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan.

Background

IgG₄-related disease (IgG₄-RD) is an immune-mediated fibrotic disorder that has been linked to CD4⁺ cytotoxic T lymphocytes (CD4⁺CTLs). The effector phenotype of CD4⁺CTLs and the relevance of both CD8⁺ cytotoxic T lymphocytes (CD8⁺CTLs) and apoptotic cell death remain undefined in IgG₄-RD.

Objective

We sought to define CD4⁺CTL heterogeneity, characterize the CD8⁺CTL response in the blood and in lesions, and determine whether enhanced apoptosis may contribute to the pathogenesis of IgG₄-RD.

Methods

Blood analyses were undertaken using flow cytometry, cell sorting, transcriptomic analyses at the population and single-cell levels, and next-generation sequencing for the TCR repertoire. Tissues were interrogated using multicolor immunofluorescence. Results were correlated with clinical data.

Results

We establish that among circulating CD4⁺CTLs in IgG₄-RD, CD27^loCD28^loCD57^hi cells are the dominant effector subset, exhibit marked clonal expansion, and differentially express genes relevant to cytotoxicity, activation, and enhanced metabolism. We also observed prominent infiltration of granzyme A–expressing CD8⁺CTLs in disease tissues and clonal expansion in the blood of effector/memory CD8⁺ T cells with an activated and cytotoxic phenotype. Tissue studies revealed an abundance of cells undergoing apoptotic cell death disproportionately involving nonimmune, nonendothelial cells of mesenchymal origin. Apoptotic cells showed significant upregulation of HLA-DR.

Conclusions

CD4⁺CTLs and CD8⁺CTLs may induce apoptotic cell death in tissues of patients with IgG₄-RD with preferential targeting of nonendothelial, nonimmune cells of mesenchymal origin.

中文翻译：

CD4+ 和 CD8+ 细胞毒性 T 淋巴细胞可能在 IgG4 相关疾病中诱导间充质细胞凋亡。

背景

IgG ₄相关疾病 (IgG ₄ -RD) 是一种免疫介导的纤维化疾病，与 CD4 ⁺细胞毒性 T 淋巴细胞 (CD4 ⁺ CTL) 相关。^{CD4 +} CTLs的效应表型和 CD8 ⁺细胞毒性 T 淋巴细胞 (CD8 ^{+ CTLs) 和凋亡细胞死亡的相关性在 IgG}₄ -RD中仍未确定。

客观的

我们试图确定 CD4 ⁺ CTL 异质性，表征血液和病变中的 CD8 ⁺ CTL 反应，并确定增强的细胞凋亡是否可能有助于 IgG ₄ -RD 的发病机制。

方法

使用流式细胞术、细胞分选、群体和单细胞水平的转录组分析以及 TCR 库的下一代测序进行血液分析。使用多色免疫荧光检查组织。结果与临床数据相关。

结果

我们确定，在 IgG _{4 -RD 中的循环 CD4}⁺ CTL 中，CD27 ^lo CD28 ^lo CD57 ^hi细胞是主要的效应子集，表现出显着的克隆扩增，并差异表达与细胞毒性、活化和增强代谢相关的基因。我们还观察到表达颗粒酶 A 的 CD8 ^{+ CTL 在疾病组织中的显着浸润和效应/记忆 CD8}⁺血液中的克隆扩增具有活化和细胞毒性表型的 T 细胞。组织研究表明，大量细胞正在经历凋亡性细胞死亡，其中不成比例地涉及间充质来源的非免疫、非内皮细胞。凋亡细胞显示 HLA-DR 显着上调。