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

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 and single-cell RNA sequencing, DNA methylation studies, and Treg suppression assays. In synovial fluid, CD4 + , CD8 + , and gd T cells expressed Th1-related markers, while 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. While synovial fluid CD4 + T cells displayed an overall Th1 phenotype, scRNA-seq uncovered heterogeneous effector and regulatory sub-populations, including interferoninduced 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.

Increased Development of Th1, Th17, and Th1.17 Cells Under T1 Polarizing Conditions in Juvenile Idiopathic Arthritis

“…JIA synovial fluid has an increase in Th1 cells, Th17 cells, abnormal CD8 + cells, and associated cytokines for oligoarticular, polyarticular, and enthesitis-arthritis subtypes ( 19 – 21 , 23 , 29 , 39 ). This parallels our T cell culture findings that T1 polarization produces Th1, Th17, and Th1.17 cells.…”

“…T1 and T17 cells and their effector cytokines are inflammatory. In polyarticular and oligoarticular JIA, more Th1 and Th17 cells are present in the synovial fluid of joints with arthritis (19)(20)(21)(22)(23). In oligoarticular JIA synovial fluid exhibits type 1 immunity skewing (23).…”

“…In polyarticular and oligoarticular JIA, more Th1 and Th17 cells are present in the synovial fluid of joints with arthritis (19)(20)(21)(22)(23). In oligoarticular JIA synovial fluid exhibits type 1 immunity skewing (23). Numbers of effector Th17 cells are elevated in synovial fluid cells in systemic JIA (24).…”

Rebooting Regulatory T Cell and Dendritic Cell Function in Immune-Mediated Inflammatory Diseases: Biomarker and Therapy Discovery under a Multi-Omics Lens

“…As mentioned above, Tregs are able to adapt to specific microenvironments, thus conditions such as excessive inflammation imprint onto Treg profile. It has been reported by two independent studies that in juvenile idiopathic arthritis (JIA), Tregs obtained from inflamed joints have a specific effector profile [ 66 , 67 ]. Both studies compared, among others, the transcriptome of Tregs from synovial fluid to those of peripheral blood of individuals with JIA.…”

“…Differential gene expression analysis revealed that Tregs in the synovial fluid express a Th1 transcriptomic signature that is characterized by the expression of transcription factor TBX21 (T-bet), chemokine receptor CXCR3 , and IL-12 receptor β2 ( IL12RB2 ). IFN-γ was also found upregulated in one of the studies [ 66 ], nevertheless, when Tregs were stimulated ex vivo they failed to produce this cytokine [ 67 ]. Despite high expression of Th1-related proteins, Tregs preserved their suppressive features as shown by the maintenance of a robust Treg-associated transcriptional program [ 66 ] and functional assays [ 66 , 67 ].…”