Th1 polarization defines the synovial fluid T cell compartment in oligoarticular juvenile idiopathic arthritis.

Amélie Julé ,Julie Ng,Pui Y Lee,Kevin Wei,Margaret H Chang,Esra Meidan,Talal Chatila,Olha Halyabar,Jeffrey Lo,Lauren A Henderson,James A Lederer,Mindy S Lo,Erin Janssen,Robert P Sundel,Kacie J Hoyt,Melissa Hazen ,Peter A Nigrović ,María Gutiérrez‐Arcelus ,Ezra Cohen ,Mary Beth Son ,Jay Roberts ,Siobhan Case ,Fatma Dedeoğlu ,Jonathan S Hausmann ,Maria Taylor

doi:10.1172/jci.insight.149185

Abstract

Oligoarticular juvenile idiopathic arthritis (oligo JIA) is the most common form of chronic inflammatory arthritis in children, yet the cause of this disease remains unknown. To understand immune responses in oligo JIA, we immunophenotyped synovial fluid T cells with flow cytometry, bulk RNA-Seq, single-cell RNA-Seq (scRNA-Seq), DNA methylation studies, and Treg suppression assays. In synovial fluid, CD4+, CD8+, and γδ T cells expressed Th1-related markers, whereas Th17 cells were not enriched. Th1 skewing was prominent in CD4+ T cells, including Tregs, and was associated with severe disease. Transcriptomic studies confirmed a Th1 signature in CD4+ T cells from synovial fluid. The regulatory gene expression signature was preserved in Tregs, even those exhibiting Th1 polarization. These Th1-like Tregs maintained Treg-specific methylation patterns and suppressive function, supporting the stability of this Treg population in the joint. Although synovial fluid CD4+ T cells displayed an overall Th1 phenotype, scRNA-Seq uncovered heterogeneous effector and regulatory subpopulations, including IFN-induced Tregs, peripheral helper T cells, and cytotoxic CD4+ T cells. In conclusion, oligo JIA is characterized by Th1 polarization that encompasses Tregs but does not compromise their regulatory identity. Targeting Th1-driven inflammation and augmenting Treg function may represent important therapeutic approaches in oligo JIA.

Highlights

Chronic inflammatory arthritis in children is often considered a single disease by those outside the field of pediatric rheumatology
In the oligo juvenile idiopathic arthritis (JIA) joint, multiple T cell lineages expressed markers associated with Th1 cells; the CD4+ T cell subset demonstrated the most profound Th1 polarization
Increased IL-17+CD4+ T cells were reported in JIA synovial fluid (SF) [7, 8, 39, 40]

Summary

Introduction

Chronic inflammatory arthritis in children is often considered a single disease by those outside the field of pediatric rheumatology. Juvenile idiopathic arthritis (JIA) is an umbrella term that encompasses 6 disease onset types as defined by the International League of Associations for Rheumatology (ILAR) criteria [1]. HLA associations and clinical characteristics further demonstrate that the term JIA includes several distinct diseases, whose underlying biological mechanisms are likely to differ [2, 3]. Despite this heterogeneity, studies evaluating JIA have often included children with multiple forms of inflammatory arthritis without stratifying by disease type. Synovial fluid (SF) samples are accessible in this disease, offering an important opportunity to study pediatric autoimmunity at the site of inflammation

Methods

Results

Conclusion