CD4+ T cell subset imbalance contributes to diabetic kidney disease progression: immunopathological mechanisms and targeted therapeutic strategies.

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.