A comprehensive review published in Rheumatology & Autoimmunity suggests that the bidirectional crosstalk between regulatory T cells (Tregs) and stromal cells functions as a central regulatory hub coordinating immune tolerance, inflammation resolution, and tissue regeneration. According to the authors, coordinated signaling through this axis ensures proper progression of repair processes; when the signaling becomes unbalanced, unresolved inflammation, pathological fibrosis, and autoimmune disease may ensue. Authored by the research team led by Zhaohui Zheng at the Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, the review integrates existing evidence on tissue-resident Treg specialization, stromal-cell heterogeneity, molecular communication, and emerging treatment strategies.
Beyond conventional immunosuppression: The reparative function of Tregs
Tregs have traditionally been viewed primarily as suppressors of excessive immune responses. The review emphasizes that tissue-resident Tregs (trTregs) fulfill a second, reparative function. Through local microenvironmental adaptation, epigenetic remodeling, and metabolic reprogramming, these cells suppress inflammation while directly guiding tissue stem cells, parenchymal cells, and stromal cells toward tissue regeneration. Different organs tailor this program to local physiological needs: for instance, skin Tregs support re-epithelialization, cardiac Tregs regulate extracellular matrix maturation after injury, lung Tregs limit inflammation following acute injury, and adipose Tregs support local metabolic homeostasis and repair.
Three modes of Treg–stromal cell interaction
The review delineates Treg-stromal cell communication through three distinct channels. First, soluble mediators exert reciprocal effects on differentiation, migration, phenotype, and function, including cytokines (TGF-β, IL-10, and IL-35), chemokines (CXCL12, CCL21), growth factors, and small molecules such as PGE2 and IDO. Second, extracellular vesicles shuttle microRNAs, proteins, and lipids between the two populations, serving as a supplemental, long-range signaling mechanism. Third, direct cell-to-cell contact enables precise bidirectional regulation, including CTLA-4 with CD80/CD86 and ICOS with ICOSL.
The review identifies conserved core pathways across these contexts. The IL-33/ST2 axis supports protective, early-phase repair but can turn pathological under persistent inflammation; sustained adenosine signaling through CD39/CD73 shifts local tissue toward an immunosuppressive, pro-fibrotic state; and chronic activation of the TGF-β/IDO axis promotes collagen deposition and multi-organ fibrosis. In normal healing these pathways are transient and tightly regulated; their chronic, unregulated activationdistinguishes normal healing from disease.
When the axis is disrupted: rheumatoid arthritis, systemic sclerosis, and inflammatory bowel disease
As the review explains, when the axis falters, it may contribute to chronic conditions across organ systems. In rheumatoid arthritis, destructive fibroblast-like synoviocytes evade Treg control, sustain the production of IL-6 and matrix metalloproteinases, and drive cartilage and bone erosion; programmed cell death signals such as PD-L1 and PD-1 further impair local Treg survival. In systemic sclerosis, Tregs shift toward a Th2-like phenotype and together with activated fibroblasts and myofibroblasts, promote collagen deposition and progressive tissue fibrosis. In inflammatory bowel disease, a Th17-like Treg phenotype, excess IL-6 and GM-CSF, and a compromised intestinal barrier turn the mucosal environment into a self-sustaining inflammatory loop.
A translational roadmap for precision immune regulation
This review outlines several converging strategies: optimized culture-expanded and gene-edited Treg therapy (such as CRISPR/Cas9 modulation of Foxp3 or IL2RA to improve stability and homing); biologics and small molecules targeting specific mediators, such as ST2 blockade, CCL2/CCR2 blockade, CCR4 blockade, and IL-10 receptor agonism; and co-infusion of mesenchymal stem cells and Tregs to establish a supportive niche. Additionally, precision medicine approaches for localized delivery of therapy, such as hydrogel-based sustained-release systems and engineered MSCs, are discussed for their potential to enhance efficacy while limiting systemic immunosuppression.
Most research has studied Tregs and stromal cells separately. This review argues that their dialogue, not either cell type alone, is the critical regulatory hub that determines whether an injury resolves or progresses to chronic fibrosis or autoimmunity. Targeting this axis could give us a way to restore healthy repair rather than to simply suppress immunity.
Rheumatology & Autoimmunity
Systematic review
Not applicable
Treg-stromal cell axis in tissue repair and autoimmune diseases: Mechanisms and clinical translation
12-Oct-2026
None.