期刊
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 147, 期 1, 页码 368-382出版社
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2020.05.022
关键词
IgG4-RD; CD4(+)CTL; CD8(+)CTL; apoptosis; CD28(lo); CD28(null)
资金
- National Institutes of Health (NIH) Autoimmune Centers of Excellence [U19 AI 110495]
- Rheumatology Research Foundation Scientist Development Award
- Scleroderma Foundation New Investigator Grant
- UCB
- Japan Society for the Promotioin of Science [JP18KK0260]
- Takeda Science Foundation
- WorkVisitGrant of theAmsterdamInfection and Immunity Institute
- NIH [AI113163]
- National Institute of Allergy and Infectious Diseases [P30AI060354]
- Cariplo Foundation
- Parker B. Francis Fellowship
- NIH Autoimmune Centers of Excellence [UM1 AI1144295]
In IgG(4)-related disease, CD4(+)CTLs and CD8(+)CTLs may induce apoptotic cell death in tissues by preferentially targeting nonendothelial, nonimmune cells of mesenchymal origin.
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.
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