Cory A Perugino1, Naoki Kaneko2, Takashi Maehara2, Hamid Mattoo3, Jesper Kers4, Hugues Allard-Chamard5, Vinay S Mahajan6, Hang Liu7, Emanuel Della-Torre8, Samuel J H Murphy9, Musie Ghebremichael9, Zachary S Wallace10, Marcy B Bolster10, Liam M Harvey10, Geetha Mylvaganam9, Yesim Tuncay9, Lloyd Liang11, Sydney B Montesi11, Xiuwei Zhang12, Akira Tinju13, Keita Mochizuki13, Ryusuke Munemura13, Mizuki Sakamoto13, Masafumi Moriyama13, Seiji Nakamura13, Nir Yosef12, John H Stone10, Shiv Pillai14. 1. Ragon Institute of MGH, MIT, and Harvard, Cambridge, Mass; Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Boston, Mass. 2. 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. 3. Ragon Institute of MGH, MIT, and Harvard, Cambridge, Mass; Immunology and Inflammation Therapeutic Area, Sanofi, Cambridge, Mass. 4. 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. 5. 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. 6. Ragon Institute of MGH, MIT, and Harvard, Cambridge, Mass; Department of Pathology, Brigham and Women's Hospital, Boston, Mass. 7. Ragon Institute of MGH, MIT, and Harvard, Cambridge, Mass; Department of Rheumatology and Immunology, First Hospital of China Medical University, Shenyang, China. 8. 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. 9. Ragon Institute of MGH, MIT, and Harvard, Cambridge, Mass. 10. Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Boston, Mass. 11. Division of Pulmonary & Critical Care Medicine, Massachusetts General Hospital, Boston, Mass. 12. University of California, Berkeley, Calif. 13. Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan. 14. Ragon Institute of MGH, MIT, and Harvard, Cambridge, Mass. Electronic address: pillai@helix.mgh.harvard.edu.
Abstract
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, CD27loCD28loCD57hi 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.
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, CD27loCD28loCD57hi 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.
Authors: Hugues Allard-Chamard; Faisal Alsufyani; Naoki Kaneko; Kelly Xing; Cory Perugino; Vinay S Mahajan; Joseph L Wheat; George S Deepe; James Loyd; Shiv Pillai Journal: J Immunol Date: 2020-12-16 Impact factor: 5.422
Authors: Jiachen Liu; Wei Yin; Lisa S Westerberg; Pamela Lee; Quan Gong; Yan Chen; Lingli Dong; Chaohong Liu Journal: Front Immunol Date: 2021-09-01 Impact factor: 7.561