IL-15 enhances functional properties and responses of CD28-negative CD4+ cytotoxic T cells expanded in Systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disorder that results in an attack by body's immune system of its own tissues, causing chronic inflammation and tissue damage. T cells play a key role in the pathogenesis of SLE, as they secrete pro-inflammatory cytokines as well as mediate direct effects on target tissues. Recently, CD4-positive T cells with cytotoxic potential were shown to be involved in autoimmune disease progression and tissue damage. However, whether this cell type expands and plays effector functions in SLE patients remain to be elucidated. Analyzing scRNA-Seq data and flow cytometry data, we find that cytotoxic CD4+CD28- T cells are present in SLE patients. We also show that these cells expand most prominently in patients affected by lupus nephritis, where they exhibit cytotoxic activity against human renal glomerular endothelial cells in vitro. In addition, our study suggest that IL-15 promotes the expansion, proliferation and cytotoxic function of CD4+CD28- T cells from SLE patients. Tofacitinib, a selective JAK3 inhibitor, inhibits the effect of IL-15 on CD4+CD28- T cells. Together, our study clearly demonstrated that CD4+ CD28- T cells characterized by proinflamamtory properties and cytolytic function expand in SLE patients, where they contribute to the renal damage. The pathogenic potential of these CD4+ CD28- T cells is driven by IL-15/IL-15R/JAK3/STAT5 signaling pathway, which may open new avenues for therapeutic intervention to prevent progression of SLE patients. ### Competing Interest Statement The authors have declared no competing interest.