Antigen-driven T cell-macrophage interactions mediate the interface between innate and adaptive immunity in histidyl-tRNA synthetase-induced myositis

Frontiers in Immunology

Immunology

Nicholas A. Young¹  Wael N. Jarjour¹  Ying Wang²  Daniel P. Reay³  Dana P. Ascherman³  Timothy B. Oriss³  Tracy Tabib³  Robert A. Lafyatis³  Paula R. Clemens⁴ 

[1] Department of Medicine, Ohio State University School of Medicine, Columbus, OH, United States;Department of Medicine, University of Miami School of Medicine, Miami, FL, United States;Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States;Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States;

关键词: myositis;    HRS (histidyl-tRNA synthetase);    T cell;    macrophage;    innate immunity;    adaptive immunity;   

DOI  :  10.3389/fimmu.2023.1238221

 received in 2023-06-11, accepted in 2023-09-04,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionPrevious work in humans has demonstrated that both innate and adaptive immune signaling pathways contribute to the pathogenesis of idiopathic inflammatory myopathy (IIM), a systemic autoimmune disease targeting muscle as well as extra-muscular organs. To better define interactive signaling networks in IIM, we characterized the cellular phenotype and transcriptomic profiles of muscle-infiltrating cells in our established murine model of histidyl-tRNA synthetase (HRS)-induced myositis.MethodsMyositis was induced in wild type (WT) and various congenic/mutant strains of C57BL/6 mice through intramuscular immunization with recombinant HRS. Histopathological, immunohistochemical, flow cytometric, and transcriptomic assessments were used to characterize the functional relationship between muscle-infiltrating cell populations in these strains lacking different components of innate and/or adaptive immune signaling. ResultsRAG1 KO mice developed markedly reduced muscle inflammation relative to WT mice, demonstrating a key requirement for T cells in driving HRS-induced myositis. While the reduction of mononuclear cell infiltrates in CD4-Cre.MyD88fl/fl conditional knockout mice and OT-II TCR transgenic mice highlighted roles for both innate and TCR-mediated/adaptive immune signaling in T cells, diminished inflammation in Lyz2-Cre.MyD88fl/fl conditional knockout mice underscored the importance of macrophage/myeloid cell populations in supporting T cell infiltration. Single cell RNA sequencing-based clustering of muscle-infiltrating subpopulations and associated pathway analyses showed that perturbations of T cell signaling/function alter the distribution and phenotype of macrophages, fibroblasts, and other non-lymphoid cell populations contributing to HRS-induced myositis.DiscussionOverall, HRS-induced myositis reflects the complex interplay between multiple cell types that collectively drive a TH1-predominant, pro-inflammatory tissue phenotype requiring antigen-mediated activation of both MyD88- and TCR-dependent T cell signaling pathways.

【 授权许可】

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Copyright © 2023 Reay, Tabib, Wang, Oriss, Young, Lafyatis, Jarjour, Clemens and Ascherman