---
title: "CD4+ T cell subset imbalance in diabetic kidney disease: mechanisms and therapeutic implications"
id: "frontiers-in-immunology-9-cd4-t-cell-subset-imbalance-contributes-to-diabetic-kidney-disease-progression"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-9-cd4-t-cell-subset-imbalance-contributes-to-diabetic-kidney-disease-progression"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1882303"
published_at: "2026-09-17T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# CD4+ T cell subset imbalance in diabetic kidney disease: mechanisms and therapeutic implications
## Provenance & Clinical Metadata
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- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1882303)
- **Published At:** 2026-09-17T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease; inflammation and immune mechanisms are increasingly recognized as central to its pathogenesis. - **CD4+ T cells** undergo skewed subset differentiation in DKD, with expansion of pro-inflammatory **Th1** and **Th17** populations and depletion of anti-inflammatory **Th2** and **Treg** populations. - The dual imbalance of Th1/Th2 and Th17/Treg shifts cytokine networks toward pro-inflammatory and pro-fibrotic states, correlating with clinical markers such as urinary albumin and eGFR decline. - Hyperglycemia, hypoxia and lipid disorders reshape epigenetic and transcriptional regulatory networks (including lncRNAs and transcription factors such as TBX21, GATA3, RORC, FOXP3) to promote pro-inflammatory polarization. - Th1 cells promote renal injury through chemokine-mediated recruitment (CXCL9/CXCL10–CXCR3, CCL5–CCR5), secretion of IFN-γ and TNF-α, and interactions with macrophages and innate signaling pathways (e.g., JAK2/STAT3, TLR4/TRIF). - Th2 cells are functionally suppressed in DKD; they secrete IL-4, IL-5, IL-9, IL-10 and IL-13 and antagonize Th1 responses via STAT6/GATA3 signaling, but Th2 cytokines (notably IL-4 and IL-13) can also upregulate TGF-β1 and extracellular matrix proteins in renal tubular cells under high-glucose conditions, potentially promoting fibrosis. - Experimental and clinical correlations implicate circulating and intrarenal chemokines, lncRNA signatures, and cytokine levels as potential biomarkers of CD4+ subset skewing and DKD progression. - The narrative review used PubMed, Web of Science and EMBASE through March 2026; selection prioritized original in vitro, in vivo and clinical studies and comprehensive reviews, but no formal quality assessment tool was applied. - Translating CD4+ T cell–targeted approaches into precise immunotherapy for DKD requires deeper mechanistic insight and rigorous clinical validation; specific therapeutic details were discussed in the source but are not fully detailed in the provided text.
## Clinical Analysis & Structured Key Points
Frontiers | CD4+ T cell subset imbalance contributes to diabetic kidney disease progression: immunopathological mechanisms and targeted therapeutic strategies REVIEW article Front. Immunol. , 17 September 2026 Sec. T Cell Biology Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1882303 Published in Frontiers in Immunology T Cell Biology 7 impact factor 11.3 citescore Editor & Reviewers Edited by F S Farhad Seif Reviewed by M L Moshe Levi M K Monireh Kamali R A Riyasat Ali Outline Figures and Tables Figure 1 View in article Figure 2 View in article Figure 3 View in article Figure 4 View in article Table 1 Summary of representative therapeutic interventions targeting CD4 + T cell subsets for DKD treatment, alongside their immunomodulatory mechanisms, experimental models, primary renal protective endpoints, CD4 + T cell-related effects, and translational limitations. View in article REVIEW article Front. Immunol. , 17 September 2026 Sec. T Cell Biology Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1882303 CD4 + T cell subset imbalance contributes to diabetic kidney disease progression: immunopathological mechanisms and targeted therapeutic strategies D Z Dingchang Zheng 1,2 † L Z Lingfei Zhang 1,3 † H L Hang Li 2 D W Deping Wang 3 C J Caihong Jiao 4 X L Xiaolong Li 5 S F Songbo Fu 6,7 * 1. CuiYing Honors College, Lanzhou University, Lanzhou, Gansu, China 2. The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China 3. The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China 4. Longnan First People’s Hospital, Longnan, Gansu, China 5. Zhangye Second People’s Hospital, Zhangye, Gansu, China 6. Department of Endocrinology, First Hospital of Lanzhou University, Lanzhou, Gansu, China 7. Gansu Provincial Clinical Research Center for Endocrine Disease, Lanzhou, Gansu, China See more Article metrics View details Abstract Diabetic kidney disease (DKD) is one of the most common microvascular complications of diabetes and a leading cause of end-stage renal disease. Recently, immune and inflammatory mechanisms have been recognized as critical in the pathogenesis of DKD, among which CD4 + T cell subset imbalance serves as a key contributor to renal inflammation and fibrosis. This narrative review synthesizes evidence from PubMed, Web of Science, and EMBASE (inception to March 2026) to provide a comprehensive overview of the immunopathological roles and molecular regulatory networks of major CD4 + T cell subsets, including T helper type 1, T helper type 2, T helper type 17 and regulatory T cells, in mediating renal injury through signature cytokines and signaling pathways. We also discuss the regulatory effects of hyperglycemia, hypoxia and lipid disorders on CD4 + T cell function, as well as the crosstalk between renal resident cells and CD4 + T cells via pathways such as programmed death-1/programmed death ligand-1 and nuclear factor-kappa B in amplifying inflammatory responses. Moreover, we outline current therapeutic strategies targeting CD4 + T cells, including traditional Chinese herbs, biologic agents, nonsteroidal mineralocorticoid receptor antagonists, sodium-glucose cotransporter 2 inhibitors and stem cell therapy, and evaluate their potential and limitations in balancing T cell subsets and alleviating renal injury. Although these approaches show promise, translating them into precise immunotherapy for DKD will require deeper mechanistic insight and rigorous clinical validation. 1 Introduction Diabetic kidney disease (DKD), the most prevalent microvascular complication of diabetes mellitus, is a leading cause of end-stage renal disease ( 1 ). With the rising global prevalence of diabetes mellitus, the total number of affected individuals is projected to exceed 783 million by 2045 ( 2 ). The consequent potential surge in DKD may pose a severe challenge to the global public health system. Clinical diagnosis and staging of DKD largely depend on characteristic alterations in renal function and structure ( 3 ). Functionally, DKD is mainly characterized by impaired renal filtration and excretion, manifested as decreased estimated glomerular filtration rate (eGFR), increased urinary albumin excretion, and azotemia. Structurally, it exhibits typical renal tissue remodeling, including diffuse or nodular thickening of the glomerular basement membrane, mesangial matrix expansion, podocyte injury, and inflammatory cell infiltration in the renal interstitium. Accumulating evidence indicates that multiple mechanisms, including glucolipid metabolism disorders, hemodynamic abnormalities, genetic susceptibility, and immune-inflammatory responses, play critical roles in the initiation and progression of DKD ( 4 – 6 ). Currently, strict glycemic control remains the foundation of clinical management for DKD ( 7 ); novel targeted agents such as sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RAs), and finerenone have demonstrated definite efficacy in the clinical treatment of DKD ( 8 – 10 ). However, relying solely on conventional hypoglycemic and organ-protective strategies fails to completely reverse inflammatory injury and disease progression in DKD. Therefore, exploring the core targets of immune-inflammatory regulation and deciphering the immunomolecular mechanisms underlying DKD progression have become pivotal directions for breaking through the current therapeutic bottlenecks. CD4 + T cells, as a major subset of T lymphocytes, serve as a pivotal regulator in immune responses and inflammatory modulation by undergoing directional differentiation and secreting specific cytokines ( 11 ). They mainly comprise helper T cells (Th, including functional subsets such as Th1, Th2, and Th17) and regulatory T (Treg) cells, which execute distinct functions in maintaining host immune homeostasis. Recent studies have demonstrated that the infiltration density of CD4 + T cells in the renal interstitium is significantly positively correlated with the severity of renal function deterioration; more importantly, the imbalanced polarization of their dominant cell subsets (particularly the typical Th1/Th2 and Th17/Treg imbalances) serves as the core driving force for triggering and amplifying local inflammatory responses in DKD ( 12 – 15 ). This subset shift directly disrupts the homeostatic balance between pro-inflammatory and anti-inflammatory cytokines, thereby triggering immune disorders and cascading inflammatory responses. Meanwhile, metabolic stressors such as hypoxia, hyperglycemia and hyperosmolarity, in conjunction with local innate immunity and cascading inflammatory responses, can further reshape the phenotypic characteristics and chemotactic infiltration capacity of CD4 + T cells ( 16 , 17 ). Although these studies have preliminarily delineated the pathogenic role of CD4 + T cells in DKD progression, the spatiotemporal dynamics and the intricate regulatory crosstalk between subsets within the complex microenvironment remain incompletely understood. In addition, although novel agents such as SGLT2i have exhibited preliminary immunomodulatory potential, precise immunotherapy targeting CD4 + T cells is still in its infancy. Therefore, deeply dissecting the CD4 + T cell-mediated immune network and its precise mechanisms underlying DKD progression, and further developing individualized precise intervention strategies targeting this axis, represents an urgent need in current basic and translational research of DKD. In this narrative review, we summarize the pathogenic mechanisms and molecular pathways underlying the involvement of distinct CD4 + T cell subsets in the initiation and progression of DKD. Furthermore, we highlight the crosstalk mechanisms between these subsets, glucolipid metabolism disorders and the renal resident cell microenvironment, aiming to delineate the complex immune-inflammatory network underlying CD4 + T cell-mediated synergistic regulation of multiple pathological factors in DKD. Finally, this review summarizes the emerging intervention strategies for DKD targeting CD4 + T cells as potential therapeutic targets, with the aim of providing theoretical support for future precision medicine translation. 1.1 Search strategy and selection criteria This narrative review was based on a comprehensive literature search conducted in the PubMed, Web of Science, and EMBASE databases from their inception to March 2026. The search used combinations of the following keywords: “diabetic kidney disease” OR “diabetic nephropathy”; “CD4 + T cells” OR “T helper cells”; “Th1,” “Th2,” “Th17,” “Treg”; “immune imbalance”; “inflammation”; “fibrosis”; “SGLT2 inhibitor”; “stem cell therapy”; and “immunotherapy.” To avoid bias, we prioritized original research articles ( in vitro , in vivo , and clinical studies) and comprehensive reviews published in English. Two authors independently screened titles and abstracts for relevance, focusing on the immunopathological roles of CD4 + T cell subsets in DKD progression and therapeutic strategies targeting these cells. The final set of references was selected by consensus among all authors. No formal quality assessment tool was applied. 2 CD4 + T cell subsets and their critical functions in DKD Inflammatory responses persist throughout the entire pathological progression of DKD. Infiltrating inflammatory cells and their secreted cytokines not only disrupt insulin signaling and exacerbate insulin resistance, but also directly drive renal tissue fibrosis and renal function decline ( 15 , 18 , 19 ). Clinical evidence indicates that the composition of CD4 + T cell subsets in the peripheral blood of patients with DKD has shifted markedly ( Figure 1 ): the proportions of pro-inflammatory subsets typified by Th1 and Th17 cells are significantly elevated, whereas the anti-inflammatory phenotypes of Th2 and Treg cells are sharply diminished ( 20 , 21 ). Consistent with this, studies in DKD mouse models have observed increased renal infiltration of Th1/Th17 cells and decreased Th2/Treg proportions, with the Th17/Treg ratio showing a significant positive correlation with key markers of renal injury, including the urinary albumin/creatinine ratio (UACR) ( 15 , 22 , 23 ). Bioinformatic analysis and experimental verification collectively demonstrate that the dual immune imbalance of Th1/Th2 and Th17/Treg arises from the synergistic disruption of epigenetic and transcriptional regulatory networks driven by hyperglycemia, which directly induces glomerulosclerosis and tubulointerstitial injury by disrupting the dynamic balance between pro- and anti-inflammatory networks ( 15 , 23 , 24 ). Specifically, the expression of Th1-related long non-coding RNAs (lncRNAs), such as IFNG-AS1 and FGD5-AS1 , and their transcription factor T-box transcription factor 21 ( TBX21 ), is upregulated, whereas the expression of the Th2-related lncRNA TH2LCRR and its transcription factor GATA-binding protein 3 ( GATA3 ) is downregulated, resulting in enhanced pro-inflammatory Th1 responses and weakened anti-inflammatory Th2 responses. Meanwhile, the expression of the Th17-related lncRNA CRNDE and its transcription factor retinoic acid-related orphan receptor C ( RORC ) is increased, promoting IL-17 secretion, whereas the expression of the Treg-related lncRNA SNHG1 and its transcription factor forkhead box protein 3 ( FOXP3 ) is decreased, leading to impaired immunosuppressive function. Together, these events ultimately constitute a dual vicious cycle characterized by excessive activation of pro-inflammatory pathways and insufficient activity of anti-inflammatory pathways. These findings indicate that the magnitude of CD4 + T cell subset skewing may serve as a potential biomarker for assessing the progression of renal injury in DKD. Herein, we discuss the pathogenic and regulatory mechanisms of each key subset during DKD progression. Figure 1 Imbalance pattern of CD4 + T cell subsets in diabetic kidney disease (DKD). In DKD microenvironment, the differentiation ratio and tissue infiltration abundance of CD4 + T lymphocytes are markedly disrupted. Pro-inflammatory T helper type 1 (Th1) and T helper type 17 (Th17) subsets expand substantially, accompanied by elevated secretion of signature pro-inflammatory cytokines including interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and interleukin-17A (IL-17A). Conversely, anti-inflammatory T helper type 2 (Th2) and regulatory T (Treg) cell populations are significantly depleted, with reduced production of protective cytokines interleukin-4 (IL-4), interleukin-10 (IL-10), and transforming growth factor-β (TGF-β). The dual imbalance of Th1/Th2 and Th17/Treg axes constitutes the core immunopathological hallmark of DKD, which continuously amplifies intrarenal inflammatory cascades and drives progressive renal fibrosis. DKD, diabetic kidney disease; Th1, T helper type 1; Th2, T helper type 2; Th17, T helper type 17; Treg, regulatory T cell; IFN-γ, interferon-γ; TNF-α, tumor necrosis factor-α; IL, interleukin; TGF-β, transforming growth factor-β. 2.1 Th1 cells Th1 cells, as the prototypical pro-inflammatory subset, primarily mediate immune and inflammatory responses by secreting effector cytokines including interferon-γ (IFN-γ), interleukin-2 (IL-2), and tumor necrosis factor-α (TNF-α) ( 25 ). At the level of differentiation regulation, serum IL-12 levels are significantly elevated in patients with DKD and closely correlated with eGFR decline, while IFNG-AS1 is upregulated in peripheral blood and positively associated with TBX21 mRNA levels and indicators of deteriorating renal function ( 15 , 20 , 23 , 24 ). These clinical findings suggest that elevated IL-12 and aberrant activation of the IFNG-AS1 / TBX21 axis may contribute to Th1 skewing, thereby exacerbating inflammatory injury in DKD. In terms of chemotactic recruitment, the directed migration of Th1 cells to the renal lesion site relies on local chemokine concentration gradients. Clinical evidence indicates that C-X-C motif chemokine ligand 9 (CXCL9) levels in the serum and urine of DKD patients are significantly higher than those in healthy controls ( 26 ). In vitro studies further revealed that advanced glycation end products (AGEs) upregulate the expression of CXCL9 and its receptor C-X-C chemokine receptor type 3 (CXCR3) in mouse podocytes, activate the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway, and induce podocyte apoptosis and inflammation ( 26 ). Animal experiments have demonstrated that the extracellular matrix component biglycan acts as an endogenous danger signal, inducing CXCL10 secretion in macrophages (Mø) via the Toll-like receptor 4/TIR-domain-containing adapter-inducing interferon-β (TLR4/TRIF) signaling pathway and promoting CXCL9 release in synergy with IFN-γ; together, these chemokines recruit CXCR3-positive Th1 and Th17 cells to infiltrate the kidney, thereby aggravating proteinuria ( 27 ). Concurrently, this same study observed a positive correlation between plasma biglycan levels and CXCL9/CXCL10 levels in DKD patients, providing clinical correlative evidence for the proposed mechanism ( 27 ). In addition, the binding of C-C motif chemokine ligand 5 (CCL5) to its receptor C-C chemokine receptor type 5 (CCR5) represents another important pathway that guides the directional migration of these cells ( 28 ). The IFN-γ and TNF-α released by Th1 cells after infiltration can mediate renal tissue damage through multiple mechanisms. Clinical studies have demonstrated a positive correlation between serum IFN-γ and TNF-α levels and urinary albumin excretion rate in DKD patients, and both cytokines have been recognized as potential molecular markers for evaluating disease severity in DKD ( 13 ). In vitro experiments have shown that AGEs markedly enhance the capacity of activated T cells to produce IFN-γ ( 29 ). Consistent with this, animal studies have confirmed massive macrophage infiltration and elevated expression of pro-inflammatory and pro-fibrotic factors in the kidneys of DKD rats ( 30 ). Among these factors, TNF-α not only alters glomerular hemodynamics and reduces filtration rate, but also directly induces podocyte and tubular cell toxicity, triggers local reactive oxygen species generation, and synergizes with transforming growth factor-beta (TGF-β) to indirectly promote renal inflammation and fibrosis ( 31 ). Notably, IFN-γ and TNF-α can further recruit and activate Mø, establishing a pro-inflammatory positive feedback loop that amplifies the local inflammatory cascade; however, the specific signaling pathways within this loop remain to be experimentally validated ( 30 ). Thus, excessive infiltration of Th1 cells and the ensuing pro-inflammatory cytokine storm represent one of the core drivers underlying the progression of early-stage DKD lesions. Nevertheless, the immune network does not operate unidirectionally, and Th2 cells, which antagonize Th1 cells, also play an indispensable role in the pathogenesis of DKD. 2.2 Th2 cells As the natural antagonist of Th1 cells, Th2 cells constitute the major anti-inflammatory subset within the CD4 + T-cell population. They not only initiate and sustain humoral immune responses but also directly suppress the activation of Th1 cells and limit the propagation of inflammatory reactions ( 32 ). Clinical cross-sectional studies have demonstrated that Th2 cell function is frequently and markedly suppressed in patients with DKD, with their counts showing a significant negative correlation with urinary protein levels ( 2 ). Clinical evidence from DKD patients further indicates that Th2 cells orchestrate a sophisticated immunoregulatory network by secreting cytokines including IL-4, IL-5, IL-9, IL-10, and IL-13 ( 13 ). Among these, the core factor IL-4 not only regulates cell proliferation and inflammatory cytokine secretion but also activates the STAT6 signaling pathway. Early studies using Stat6 -deficient mice established that IL-4-induced STAT6 activation is a key event for Th2 cell differentiation and GATA3 upregulation ( 33 – 35 ). Subsequently, Zheng and Flavell, employing retroviral overexpression and antisense oligonucleotide techniques in mouse CD4 + T cells in vitro , demonstrated that GATA3 is both necessary and sufficient to drive Th2 cytokine gene expression ( 36 ). Meanwhile, in vitro experiments have shown that IL-4 upregulates the expression of the IL-4 receptor α-chain (IL-4Rα) on the surface of Th2 cells, forming an IL-4/IL-4Rα positive feedback loop that enhances the responsiveness of Th2 cells to IL-4 ( 37 ). Furthermore, in vitro studies collectively revealed that IL-2, produced by activated T cells, activates the STAT5 pathway and cooperates with GATA3 to drive sustained Th2 cytokine production, which is critical for Th2 differentiation ( 38 , 39 ). It should be noted that all of the above positive feedback regulatory mechanisms have been established in mouse T cell in vitro differentiation systems, and direct experimental validation in the DKD renal microenvironment is currently lacking. However, the effects of Th2 cell-derived cytokines are not universally beneficial, with IL-13 serving as a notable example. In patients with DKD, serum IL-13 levels decline significantly as nephropathy progresses, suggesting that this cytokine may be consumed or suppressed under disease conditions ( 20 ). In vitro experiments have shown that recombinant IL-4 and IL-13 can directly act on human renal tubular epithelial cells (RTCs) to upregulate the expression of TGF-β1, fibronectin, and type I collagen; furthermore, under high glucose conditions, both IL-4 and IL-13 synergize with hyperglycemia to markedly enhance the production of these pro-fibrotic factors ( 40 ). From a dose-response perspective, IL-4 upregulates TGF-β1 and fibronectin in HK-2 cells in a concentration- and time-dependent manner ( 40 ). Collectively, these findings
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