Senescent CD4⁺ T cells and autoimmune diseases: mechanisms and therapeutic prospects

Senescent CD4⁺ T cells exhibit classical features of T-cell senescence-including telomere attrition, reduced proliferative capacity, and an upregulated senescence-associated secretory phenotype (SASP)-while also displaying unique characteristics. Notably, they maintain relatively healthy mitochondrial mass compared with senescent CD8⁺ T cells, a distinction that influences their roles in immune regulation and tissue pathology. Multiple signaling pathways, such as the ATM-DDR-p53 axis, AMPK-TAB1-p38 cascade, mTOR signaling, mitochondrial-ROS axis, and IL-7/IL-2 cytokine networks, are dysregulated during the senescence of CD4⁺ T cells. Importantly, senescent CD4⁺ T cells can promote chronic inflammation, disrupt immune homeostasis, and remodel tissue microenvironments through the secretion of SASP components (e.g., IL-6, IL-8, TNF-α, and MMPs). They also have the potential to enhance antibody secretion by B cells, ultimately contributing to tissue-specific damage. These aberrant cells have been shown to accumulate in several autoimmune diseases (ADs), including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and systemic sclerosis (SSc). Targeting senescent CD4⁺ T cells with senotherapeutic agents and SASP inhibitors has been shown to markedly suppress AD progression, underscoring the translational potential of this therapeutic approach. However, more specific senescence markers are needed to accurately identify senescent CD4⁺ T cells. This review synthesizes current knowledge on senescent CD4⁺ T cells and their involvement in autoimmune diseases. Future research should prioritize elucidating their pathogenic mechanisms and developing targeted therapeutic strategies to mitigate their detrimental effects in ADs.