Abstract

Abstract Background CD4+ T cell hyperactivation is a pivotal driver of systemic autoimmunity in systemic lupus erythematosus (SLE), yet the molecular regulators that set its activation threshold remain poorly defined. Methods PPP2R3C expression was measured by qRT‐PCR and Western blotting in CD4+ T cells from 45 SLE patients and 37 healthy controls, as well as in pristane‐induced lupus (PIL) mice. Jurkat cells with PPP2R3C knockdown or overexpression were generated by lentiviral transduction. Signaling mechanisms were dissected using transcriptome sequencing and calcium flux assays. In vivo, PPP2R3C was restored in PIL mice via T cell‐targeted Ark313 vector or systemic AAV9 delivery; disease progression was assessed at 24 and 48 weeks after pristane induction. Results We identified the protein phosphatase 2A regulatory subunit PPP2R3C as a critical and selective negative regulator of T cell receptor (TCR) signaling, which was downregulated in CD4+ T cells from SLE patients and pristane‐induced lupus (PIL) mice. Reduced PPP2R3C expression was also observed in the kidneys of both PIL mice and lupus nephritis patients. In PIL mice, this reduction was evident in podocytes, endothelial cells, and mesangial cells, indicating widespread downregulation across kidney resident cell populations. Mechanistically, PPP2R3C deficiency enhanced T cell activation, cytokine production, and calcium flux by potentiating PLCγ1 phosphorylation and subsequent TCR‐driven JNK/c‐Jun signaling, whereas its overexpression produced opposing effects. To assess therapeutic potential, we restored PPP2R3C expression in PIL mice using two complementary gene delivery strategies. T cell‐targeted reconstitution via the Ark313 vector potently suppressed T cell activation and autoantibody production at an early stage (24 weeks), culminating in markedly attenuated proteinuria and glomerular immune complex deposition by late‐stage disease (48 weeks).