Infiltration Profile of Regulatory T Cells in Osteoarthritis-Related Pain and Disability

Abstract

Emerging evidence indicates that regulatory T cells (Treg) intervene in the inflammatory processes that drive osteoarthritis (OA). However, whether polarized Tregs affect clinical features of the disease in the short- or long-term, and if so, what their role in OA-related pain and functional disability really is, remains elusive. Thus, the aim of the current study was to characterize the infiltration profile of Tregs in systemic (peripheral blood) and joint-derived (synovial fluid and synovial membrane) samples from patients with knee OA in relation to OA-induced symptoms. To this end, Treg infiltration (CD4+CD25+/high CD127low/−) was analyzed in matched samples of peripheral blood (PB), synovial fluid (SF) and synovial membrane (SM) from a total of 47 patients undergoing elective knee arthroplasty using flow cytometry. At the same time, knee pain and function were assessed and correlated with Treg proportions in different compartments (PB, SF, SM). Interestingly, matched-pair analysis revealed significantly higher Treg proportions in joint-derived samples than in PB, which was mainly attributed to the high Treg frequency in SF. Moreover, we found significant associations between infiltrating Tregs and OA-related symptoms which indicate that lower Treg proportions—especially in the SM—are related to increased pain and functional disability in knee OA. In conclusion, this study highlights the importance of local cellular inflammatory processes in OA pathology. Intra-articular Treg infiltration might play an important role not only in OA pathogenesis but also in the development of OA-related symptoms.

OA susceptibility in mice is partially mediated by the gut microbiome, is transferrable via microbiome transplantation and is associated with immunophenotype changes

“…Indeed, our immunophenotyping results indicate that mouse groups protected from OA have expansions of peripheral CD25+CD4+ T cells, which are likely Tregs, although definitive identification will require further characterisation, including intracellular Foxp3 expression in future studies. Previous studies on Tregs in OA have been somewhat contradictory; on the one hand, increases in joint-infiltrating Tregs correlate positively with OA symptoms,53 although this study noted a significantly increased number of Tregs in joint tissues compared with peripheral blood, indicating that recruitment of Tregs may be a reactive process related to ongoing inflammation rather than a primary change. Furthermore, adoptive transfer of Col II-specific anti-inflammatory Tregs protect mice from OA,54 and peripheral blood T-regs are decreased in knee OA patients 55…”

Causal relationships between CD25 on immune cells and hip osteoarthritis

“…Although OA has historically been considered a non-inflammatory degenerative disease, emerging evidence underscores the role of immune-related factors in its pathogenesis, with their active involvement in the inflammatory processes underlying OA. Therefore, the attenuation of anti-inflammatory effects and the enhancement of pro-inflammatory effects can both exacerbate the progression of inflammation, thereby driving the advancement of OA ( 7 – 10 , 39 , 40 ). CD25, a pivotal immune-related component, serves as the α chain of the IL-2R and is predominantly present on the surface of activated T cells, B cells, and NK cells.…”

“…For instance, an exploration into mesenchymal stem cell (MSC) therapy for OA revealed that treatment engendered the accumulation of CD4 + CD25 + leukocyte subsets within the joints, effectively mitigating OA progression ( 41 ). Similarly, a distinct study demonstrated that OA patients exhibit lower proportions of CD4 + CD25 + Tregs compared to healthy individuals, potentially contributing to increased pain and functional impairment ( 39 ). While previous studies have reported a significant increase in CD8 + CD25 + T cells in patients with rheumatoid arthritis, which exacerbates the progression of inflammation and may be an important pathogenic mechanism ( 42 ).…”

Bioinformatics-based analysis of potential candidates chromatin regulators for immune infiltration in osteoarthritis

“…Recent studies suggest that dysregulation of the immune system in obese patients may exacerbate the inflammatory response to OA [24]. Immune cells also play a regulatory role in the development of OA-related symptoms [25]. Nees et al [25] found that a lower percentage of Treg in the synovial membrane was associated with increased pain and functional impairment in knee OA.…”

“…Immune cells also play a regulatory role in the development of OA-related symptoms [25]. Nees et al [25] found that a lower percentage of Treg in the synovial membrane was associated with increased pain and functional impairment in knee OA.…”