T-cell–driven immune modulation in osteoarthritis: deciphering the hADSC–macrophage cross-talk

Vollständiger Abstract

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Abstract Osteoarthritis (OA) has traditionally been regarded as a mechanically driven degenerative joint disorder. However, recent advances in single-cell sequencing, spatial omics, and immunohistochemical analyses have revealed that OA is also characterized by persistent low-grade inflammation and complex immune dysregulation involving multiple joint-resident and infiltrating cell populations. Among these, T cells, synovial macrophages, and mesenchymal stromal cells (MSCs) form a dynamic regulatory network. Within the T-cell compartment, two distinct immunoregulatory axes are dysregulated in OA: the Th1/Th2 axis (skewed toward a Th1-dominant pro-inflammatory state) and the Th17/Treg axis (characterized by excessive Th17 activity and impaired Treg function). B cells, although less studied, may also contribute to synovial inflammation through antibody production and cytokine secretion. Among different MSC populations, human adipose-derived stem cells (hADSCs), a readily accessible MSC source with potent immunomodulatory, anti-inflammatory, and tissue-reparative properties, have emerged as promising therapeutic candidates for OA. Their ability to regulate both innate and adaptive immune responses positions them as key modulators of the osteoarthritic immune microenvironment. Here, we synthesize current evidence on the role of T-cell infiltration in OA, the mechanisms governing macrophage polarization, and the bidirectional crosstalk between hADSCs and immune cells through cytokines, chemokines, exosomal microRNAs, and metabolic reprogramming. We further propose an integrated model of a T cell–macrophage–hADSC tripartite immune communication axis, in which macrophages serve as intermediary hubs, T cells act as upstream drivers of imbalance, and hADSCs function as microenvironment remodelers. This conceptual framework provides a mechanistic basis for understanding OA progression and may support the rational design of hADSC-based interventions.