Plasma Exosomal LncRNA XIST Impairs CD4⁺ T Cell Autophagy and Promotes Activation via the miR-98/RICTOR/Akt-mTOR Axis...

Systemic lupus erythematosus (SLE) is characterized by immune dysregulation driven in part by aberrant CD4⁺ T cell activation and defective autophagy. Although exosomes are increasingly recognized as mediators of immune communication, the contribution of exosomal long non-coding RNAs (lncRNAs) to T cell dysfunction in SLE remains poorly defined. This study investigated the pathogenic role and mechanism of plasma exosomal lncRNA XIST in regulating CD4⁺ T cell autophagy and activation.

Quantitative reverse transcription PCR (qRT-PCR) was used to quantify lncRNA XIST levels in plasma exosomes, while Western blotting, flow cytometry, and enzyme-linked immunosorbent assay (ELISA) were employed to assess the effects of exosomes on CD4⁺ T cell function. Gain- and loss-of-function approaches were applied to elucidate the underlying molecular mechanisms.

LncRNA XIST was significantly overexpressed in SLE plasma exosomes and positively correlated with disease activity. These exosomes enhanced lncRNA XIST expression in CD4⁺ T cells from healthy controls (HCs), leading to suppressed autophagy and increased activation. Similar effects were observed with engineered HC plasma exosomes overexpressing lncRNA XIST. Conversely, silencing lncRNA XIST in SLE CD4⁺ T cells promoted autophagy and reduced activation, although these changes were reversed upon treatment with autologous plasma exosomes. Mechanistically, exosomal XIST functioned as a molecular sponge for miR-98, upregulating RICTOR and activating the Akt/mTOR signaling pathway, thereby modulating CD4⁺ T cell function.

Plasma exosomal lncRNA XIST impairs CD4⁺ T cell autophagy and promotes activation through the miR-98/RICTOR/Akt-mTOR axis, representing a mechanistically defined candidate biomarker and potential therapeutic target in SLE.