Protein-Level and Proteomics-Supported Signatures of Human CD4+ Regulatory T Cells: Evidence, Tissue Context, and Translational Readiness in Aging and Age-Associated Disease

Regulatory CD4+ T cells (Tregs) are essential for immune tolerance, tissue repair, and control of inflammation, but functional human Tregs cannot be identified reliably by a single protein. This targeted narrative review evaluates protein-level and proteomics-supported Treg signatures with explicit attention to species, sample source, analytical platform, validation strategy, and intended use. Primary human LC-MS/MS studies reveal pathway-level differences involving T-cell receptor signaling, metabolism, lysosomal activity, and lineage protection, whereas murine proteomic studies provide mechanistic candidates such as Themis1 but do not establish human biomarkers. CyTOF, functional single-cell protein profiling, spatially resolved protein imaging, and multi-omics further resolve phenotypic and tissue heterogeneity. Established CD25high/CD127low/FOXP3-based panels support enrichment and phenotyping; CTLA-4, ICOS, TIGIT, GITR, PD-1, chemokine receptors, suppressive enzymes, metabolic proteins, and emerging candidates report functional or tissue states but are not Treg-exclusive. Cancer currently provides the strongest tissue-level and prognostic evidence, whereas data in healthy aging, cardiovascular and metabolic disease, osteoarthritis, and neurodegeneration remain heterogeneous and mainly exploratory. Across contexts, validated diagnostic sensitivity, specificity, reference ranges, prospective clinical utility, and inter-laboratory reproducibility are largely absent. Treg immunoproteomics is therefore best regarded as a discovery and stratification framework rather than a standardized clinical diagnostic test.