Core cellular modules of the immune tolerance network.
| Cell type | Key metabolic program | Key epigenetic features | Functional outcome | References |
|---|---|---|---|---|
| Regulatory T cells (Tregs) | Oxidative phosphorylation (OXPHOS); fatty-acid oxidation (FAO); high NAD+; AMPK-SIRT1 signaling | FOXP3 CNS2 demethylation; repressive histone marks at effector loci | Maintenance of immune suppression and tolerance stability | [12, 37] |
| Regulatory B cells (Bregs) | Balanced glycolysis/OXPHOS; low ROS | BLIMP-1-dependent chromatin program | Suppression of humoral autoimmunity and control of germinal-center responses | [38, 39] |
| Tolerogenic dendritic cells (tolDCs) | OXPHOS-dominant; IDO1-kynurenine pathway | Reduced H3K27ac at costimulatory loci; tolerogenic enhancer landscape | Induction of Tregs and peripheral tolerance | [40–42] |
| M2-like macrophages | OXPHOS; low succinate; low HIF-1α | Repressive chromatin at inflammatory gene loci | Tissue repair, anti-inflammatory signaling, and resolution of inflammation | [43–45] |
| Fibroblast-like synoviocytes (FLS) | Increased glycolysis; altered mitochondrial/OXPHOS balance in inflammatory states | Epigenetic activation of inflammatory and tissue-remodeling programs, including EZH2- and non-coding RNA-associated regulation | Stromal activation, inflammatory mediator production, matrix remodeling, and persistence of synovial inflammation | [46–48] |
| Stromal & endothelial cells | Oxidative tissue niche; retinoic acid and kynurenine production | Repressed adhesion molecule loci (ICAM1/VCAM1) | Regulation of immune-cell trafficking and tissue-level equilibrium | [49, 50] |
AMPK: AMP-activated protein kinase; BLIMP-1: B lymphocyte-induced maturation protein 1; CNS2: conserved non-coding sequence 2; FOXP3: forkhead box P3; HIF-1α: hypoxia-inducible factor-1 alpha; ICAM1: intercellular adhesion molecule 1; IDO1: indoleamine 2,3-dioxygenase 1; ROS: reactive oxygen species; SIRT1: sirtuin 1.
OAA: Conceptualization, Investigation, Visualization, Writing—original draft. MMN: Conceptualization, Investigation, Methodology, Project administration, Supervision, Validation, Visualization, Writing—original draft, Writing—review & editing. Both authors read and approved the submitted version.
The authors declare no conflict of interest.
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