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

Abstract

Introduction:

Previous 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.

Methods:

Myositis 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.

Results:

RAG1 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.

Discussion:

Overall, 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.

• Authors: Daniel P Reay, Tracy Tabib, Ying Wang, Timothy B Oriss, Nicholas A Young, Robert A Lafyatis, Wael N Jarjour, Paula R Clemens, Dana P Ascherman
• Journal: Frontiers in immunology (Front Immunol) Vol. 14 Pg. 1238221 ( 2023) ISSN: 1664-3224 [Electronic] Switzerland
• PMID: 37809058 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2023 Reay, Tabib, Wang, Oriss, Young, Lafyatis, Jarjour, Clemens and Ascherman.

Chemical References

• Histidine-tRNA Ligase
• Receptors, Antigen, T-Cell

Topics

• Humans
• Mice
• Animals
• Histidine-tRNA Ligase
• T-Lymphocytes
• Mice, Inbred C57BL
• Myositis
• Adaptive Immunity
• Macrophages
• Inflammation
• Mice, Knockout
• Receptors, Antigen, T-Cell