New T Cell Subset Linked to Bone Loss in Rheumatoid Arthritis, Offering Novel Therapeutic Target

A newly identified subset of regulatory T cells, known as iTr35 cells, may play a critical role in protecting against bone loss in patients with rheumatoid arthritis (RA), according to a prospective study published in the Annals of Medicine. The findings not only shed light on the immunologic mechanisms behind skeletal deterioration in RA, but also open the door to innovative treatment strategies aimed at preserving bone health through immune modulation.

Although the role of conventional regulatory T (Treg) cells in suppressing osteoclastogenesis is well established, the function of non-classical T cell subsets—particularly iTr35 cells—has remained largely unexplored.

iTr35 cells are a recently characterized population of inducible, IL-35-producing CD4⁺ T cells that lack Foxp3 expression and instead rely on the expression of Ebi3 and IL-12p35, the subunits of the immunosuppressive cytokine IL-35. Unlike traditional Tregs, iTr35 cells operate in a contact-independent, Foxp3-independent manner and have shown regulatory roles in various autoimmune and inflammatory conditions. However, their involvement in bone metabolism in RA was not previously known.

To investigate this, researchers at Shengjing Hospital of China Medical University conducted a case-control study involving 34 treatment-naïve RA patients and 34 healthy controls matched by age and sex. Using flow cytometry, the team quantified iTr35 cells in peripheral blood and assessed bone health via dual-energy X-ray absorptiometry (DXA) and serum bone turnover markers.

The results were striking: RA patients had significantly lower frequencies of circulating iTr35 cells compared to healthy individuals. Moreover, iTr35 levels showed a strong inverse correlation with bone mineral density (BMD) at both the lumbar spine (r = −0.6162, p = 0.0001) and femoral neck (r = −0.6421, p < 0.0001). Lower iTr35 levels were also associated with elevated concentrations of TRAP5b and CTX-I, markers of osteoclast activity, and decreased levels of osteocalcin, a marker of bone formation.

Multivariate regression analysis confirmed that iTr35 frequency was an independent predictor of femoral neck BMD, even after adjusting for age, body mass index, and postmenopausal status. This finding underscores the possibility that iTr35 deficiency contributes directly to bone loss in RA, rather than merely reflecting systemic inflammation.

To better conceptualize this mechanism, the authors proposed an immune-skeletal regulatory axis. In healthy individuals, abundant iTr35 cells promote IL-35 production, suppressing osteoclast differentiation by inhibiting the RANKL-NFATc1 signaling pathway and downregulating pro-inflammatory cytokines like IL-17 and TNF-α. In contrast, RA patients exhibit iTr35 cell depletion, which may tip the immune balance toward unchecked bone resorption.

These findings not only add a new layer of complexity to the understanding of osteoimmunology but also highlight iTr35 cells as promising targets for future therapeutic development. Current disease-modifying antirheumatic drugs (DMARDs) primarily suppress inflammation, yet have limited success in halting systemic bone loss. The ability to stimulate iTr35 cell activity or enhance IL-35 signaling could offer a two-pronged approach: controlling inflammation while preserving skeletal integrity.