PPP2R3C serves as a negative regulator associated with reduced T cell hyperactivation and renal protection in lupus

BACKGROUND: 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: 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: 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). Systemic delivery of AAV9-PPP2R3C provided comprehensive therapeutic effects, ameliorating renal pathology while also normalizing immune dysregulation in both the thymus and spleen across both time points. CONCLUSIONS: Our findings identify PPP2R3C as an important contributor to SLE pathogenesis and support its restoration as a gene therapy approach worthy of further exploration for its ability to rebalance immunity and mitigate tissue injury in SLE. KEY POINTS: T cells and correlates with disease activity. It restrains the PLCγ1-JNK axis to limit T cell hyperactivation and cytokine production. Gene therapy restoring PPP2R3C suppresses autoimmunity and lupus nephritis in mice, and its reduction in kidney resident cells indicates a direct renoprotective effect, positioning PPP2R3C as a promising therapeutic target for SLE.