Immunologic Profiling Suggests an Association Between Treg Cell Dysfunction and Pain in Knee Osteoarthritis

Pain is the hallmark symptom of osteoarthritis (OA), and its biologic drivers remain poorly understood. Although the role of innate immunity in OA has been extensively studied, the involvement of adaptive immunity, in particular Treg cells, is not well understood.

We performed omics profiling of peripheral blood from 46 patients with knee OA with similar radiographic stage, including deep immunophenotyping, cytokine profiling, transcriptomics, and T cell receptor analysis on sorted CD4+ Treg cells and Teff cells.

We identified an immunologic signature associated with OA-related pain. Cytokines promoting Treg expansion and activation (with increases of sIL2-RA, sTNFR1, and sTNFR2) were correlated with the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain subscore, suggesting a potential Treg dysfunction. Nineteen T cell subsets were correlated with WOMAC pain. Notably, we found a negative correlation of cell subsets associated with Treg expansion and activation (FoxP3+CTLA4+, CD4+CD57+, Treg CD95+, and CD4 Treg CD45RA-). Differential gene expression analysis between patients with low and high WOMAC pain intensity (threshold ≥40/100) revealed an upregulation of inflammasome-related genes such as IL1RL1, IL31RA, IFITM3, NLRP3, and IFNG in Treg cells. Functional enrichment analysis highlighted an overrepresentation of innate immune response, interleukin-8, and interferon activation and pro-inflammatory genes in the Treg cells of patients with high pain intensity.

Collectively, our systems immunology approach highlights potential associations between Treg dysfunctionality and OA-related pain, providing new hypotheses into the adaptive immune system's contribution to OA-related pain.