Increased CaMK4 Activity Drives Excessive CD8+ T-Cell Cytotoxicity in Systemic Lupus Erythematosus 2306645

Abstract

Abstract Introduction Calcium/calmodulin-dependent kinase IV (CaMK4) modulates key immune pathways central to the development and amplification lupus pathology, including IL-2 suppression, elevated IL-17, Treg—Th17 imbalance, and Tfh-driven B-cell responses in lupus patients and lupus prone mice. However, its role in regulating cytotoxic CD8+ T-cell activity in lupus remains unclear, prompting our aim to define how CaMK4 shapes CD8+ effector functions and contributes to disease progression. Methods CD8+ T cells from SLE patients, MRL/lpr mice, and Camk4⁻/⁻ mice were analysed for cytotoxic markers by flow cytometry. CaMK4 was inhibited genetically or pharmacologically, and cytotoxicity was assessed by degranulation, killing, and cytokine assays. Results Analysis of CD8+ T cells from the peripheral blood of patients with SLE revealed an elevateion of CaMK4 expression compared with healthy controls. In MRL/lpr mice, CD8+ T cells isolated from kidneys of older, clinically affected animals, exhibited increased CaMK4 levels relative to younger, presymptomatic mice or splenocytes, suggesting a disease and tissue-associated upregulation. Consistent with these observations, injection of an anti-glomerular basement membrane (GBM) into B6 normal mice induced a similar pattern of increased CaMK4 expression in renal CD8+ T cells including those from kidney draining lymph nodes. Functional studies comparing CD8+ T cells from Camk4⁻/⁻ and B6 mice showed a notable reduction cytotoxic molecules and killing capacity in the absence of CaMK4. Furthermore, pharmacologic inhibition using KN-93 significantly reduced phosphorylated (p)CaMK4, the active kinase form, resulting in a parallel decrease in cytotoxic cytokines such as IFNg, GZMB and Perforin. Conclusion These findings reveal that increased CaMK4 expression in CD8+ T cells accounts for enhanced cytotoxicity in lupus, and that its blockade reduces pathogenic effector functions. Our studies reveal a previously unrecognised regulatory pathway governing CD8+ T-cell activity in lupus. Funding Source n/a Topic Categories Basic Autoimmunity (BA)