CD4(+) and CD8(+) cytotoxic Tlymphocytes may induce mesenchymal cell apoptosis in IgG(4)-related disease

Autor: Yesim Tuncay, Liam Harvey, Akira Tinju, Vinay Mahajan, Hugues Allard-Chamard, Samuel J.H. Murphy, Cory A. Perugino, Jesper Kers, Takashi Maehara, Seiji Nakamura, Ryusuke Munemura, Xiuwei Zhang, Emanuel Della-Torre, Mizuki Sakamoto, Hang Liu, Sydney B. Montesi, Zachary S. Wallace, Musie Ghebremichael, Lloyd L. Liang, Keita Mochizuki, John H. Stone, Geetha H. Mylvaganam, Masafumi Moriyama, Shiv Pillai, Nir Yosef, Naoki Kaneko, Hamid Mattoo, Marcy B. Bolster
Přispěvatelé: Pathology, AII - Inflammatory diseases, APH - Digital Health, APH - Global Health, Perugino, Ca, Kaneko, N, Maehara, T, Mattoo, H, Kers, J, Allard-Chamard, H, Mahajan, V, Liu, H, DELLA TORRE, E, Murphy, Sjh, Ghebremichael, M, Wallace, Z, Bolster, Mb, Harvey, Lm, Mylvaganam, G, Tuncay, Y, Liang, L, Montesi, Sb, Zhang, X, Tinju, A, Mochizuki, K, Munemura, R, Sakamoto, M, Moriyama, M, Nakamura, S, Yosef, N, Stone, Jh, Pillai, S.
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Journal of Allergy and Clinical Immunology, 147(1), 368-382. MOSBY-ELSEVIER
Journal of allergy and clinical immunology, 147(1), 368-382. Mosby Inc.
ISSN: 0091-6749
Popis: Background: IgG(4)-related disease (IgG(4)-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 IgG(4)-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 IgG(4)-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 IgG(4)-RD, CD27(lo)CD28(lo)CD57(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 IgG(4)-RD with preferential targeting of nonendothelial, nonimmune cells of mesenchymal origin.
Databáze: OpenAIRE
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