Diabetic kidney disease (DKD) is a common microvascular complication of diabetes and a leading cause of end-stage renal disease. Immune and inflammatory mechanisms have emerged as important contributors to DKD pathogenesis. In particular, imbalance among CD4+ T cell subsets — with expansion of pro-inflammatory Th1 and Th17 populations and depletion of anti-inflammatory Th2 and Treg cells — drives intrarenal inflammation and fibrosis. This review synthesizes literature through March 2026 on the immunopathological roles of major CD4+ T cell subsets, their regulatory networks (including lncRNAs and transcription factors), modulation by metabolic stressors, chemokine-guided recruitment, and the translational challenges for therapies targeting these cells.
DKD is characterized clinically by declining estimated glomerular filtration rate (eGFR), increased urinary albumin excretion, and azotemia, and structurally by glomerular basement membrane thickening, mesangial expansion, podocyte injury, and interstitial inflammatory infiltration. Multiple mechanisms contribute to DKD, including glucolipid metabolism disorders, hemodynamic changes, genetic susceptibility and immune-inflammatory responses. Although glycemic control and agents such as sodium-glucose cotransporter 2 inhibitors (SGLT2i), GLP-1 receptor agonists and finerenone provide benefit, inflammatory injury is not fully reversed by current standard therapies. Thus, defining immune-inflammatory core targets—particularly among CD4+ T cells—is an urgent research priority.
The review summarized here was based on searches of PubMed, Web of Science and EMBASE from inception to March 2026 using terms including “diabetic kidney disease” or “diabetic nephropathy”; “CD4+ T cells” or “T helper cells”; “Th1,” “Th2,” “Th17,” “Treg”; and terms related to inflammation, fibrosis and therapeutic interventions. Priority was given to original in vitro, in vivo and clinical studies and comprehensive reviews published in English. Two authors independently screened records for relevance and all authors reached consensus on the final selection. No formal quality-assessment tool was applied.
Persistent inflammatory responses accompany DKD progression. Clinical and preclinical evidence shows a consistent pattern: increased proportions of pro-inflammatory Th1 and Th17 cells and decreased proportions of anti-inflammatory Th2 and Treg cells in peripheral blood and renal tissue. The skewed Th1/Th2 and Th17/Treg balance shifts cytokine milieu toward IFN-γ, TNF-α and IL-17A and away from IL-4, IL-10 and TGF-β, amplifying intrarenal inflammatory cascades and promoting fibrosis. Epigenetic and transcriptional disturbances driven by metabolic stressors (hyperglycemia, hypoxia, lipid disorders) — including altered long non-coding RNA expression and changes in lineage-defining transcription factors — underpin this subset redistribution.
In DKD, bioinformatic and experimental data point to coordinated dysregulation of lncRNAs and transcription factors that favor pro-inflammatory polarization. Examples detailed in the source include upregulation of Th1-associated lncRNAs (e.g., IFNG-AS1, FGD5-AS1) and TBX21, downregulation of Th2-associated lncRNA TH2LCRR and GATA3, increased Th17-related CRNDE and RORC, and decreased Treg-associated SNHG1 and FOXP3. This dual immune imbalance forms a vicious cycle of excessive pro-inflammatory activation and inadequate anti-inflammatory control. The degree of CD4+ subset skewing correlates with renal injury markers such as urinary albumin/creatinine ratio (UACR), suggesting potential biomarker utility.
Th1 cells are a prototypical pro-inflammatory CD4+ subset that secrete IFN-γ, IL-2 and TNF-α. Clinical studies show elevated serum IL-12 and upregulated IFNG-AS1/TBX21 expression in DKD patients, which associate with eGFR decline and may promote Th1 skewing. Recruitment of Th1 cells to renal tissue is mediated by chemokine gradients: elevated CXCL9 and CXCL10 levels and upregulation of CXCR3 have been observed in DKD contexts. Advanced glycation end products (AGEs) can upregulate CXCL9/CXCR3 and activate JAK2/STAT3 signaling in podocytes, promoting apoptosis and inflammation. Biglycan and TLR4/TRIF–dependent macrophage signals can further induce CXCL10 and synergize with IFN-γ to recruit CXCR3+ Th1/Th17 cells. Th1-derived IFN-γ and TNF-α correlate with urinary albumin excretion clinically and contribute to renal damage by altering glomerular hemodynamics, inducing podocyte and tubular cell toxicity, generating reactive oxygen species, and cooperating with TGF-β to promote fibrosis. These cytokines also recruit and activate macrophages, establishing pro-inflammatory feedback loops; however, the precise signaling nodes within such loops require further experimental validation.
Th2 cells act as functional antagonists to Th1 and are important anti-inflammatory regulators. Clinical data indicate suppressed Th2 function in DKD, with Th2 counts negatively correlated with proteinuria. Th2-derived cytokines include IL-4, IL-5, IL-9, IL-10 and IL-13. IL-4 drives STAT6 activation and GATA3 upregulation, promoting Th2 differentiation; IL-2/STAT5 signaling cooperates with GATA3 to sustain Th2 cytokine expression in experimental systems. Notably, some Th2 cytokines may exert pro-fibrotic effects in the renal microenvironment: in vitro, recombinant IL-4 and IL-13 induce TGF-β1, fibronectin and type I collagen expression in human renal tubular epithelial cells (HK-2), and synergize with high glucose to amplify production of these pro-fibrotic factors. Serum IL-13 declines with DKD progression, suggesting altered regulation or consumption in disease.
The reviewed evidence positions CD4+ T cell subset imbalance as a central immunopathological driver in DKD. Altered lncRNA–transcription factor networks, chemokine-mediated recruitment and metabolic stressors all contribute to subset skewing and renal injury. While the source discusses therapeutic approaches targeting CD4+ T cells (including traditional Chinese herbs, biologics, SGLT2i, mineralocorticoid receptor antagonists and stem cell therapy) and notes preliminary immunomodulatory potential, detailed therapeutic efficacy and translational pathways were not fully reported in the provided text. The authors emphasize that precise immunotherapy for DKD will require deeper mechanistic insight, validation of molecular targets in the renal microenvironment, and rigorous clinical trials to confirm safety and efficacy.