Excessive IL-15 promotes cytotoxic CD4 + CD28- T cell-mediated renal injury in lupus nephritis

Patients with systemic lupus erythematosus (SLE) are highly susceptible to infection and cardiovascular events, suggesting that chronic antigenic stimulation may accelerate premature aging in SLE patients. Premature aging in SLE is often accompanied with the expansion of cytotoxic CD4 + CD28-T cells. Damage caused by CD4 + CD28- T cells enhances the progressive aging of the tissue function and loss of organism's fitness. The high serum level of IL-15 has been implicated in the pathogenesis of SLE, but its role in CD4 + CD28-T cell-mediated cytotoxicity in nephritic SLE remains unclear. The aim of this study was to investigate the effect of IL-15 on functional properties and associated renal damage of cytotoxic CD4 + CD28- T cell in lupus nephritis (LN).

Flow cytometry showed that the number of circulating innate-like CD4 + CD28- T cells was increased in patients with nephritic SLE. Immunofluorescence showed CD4 + CD28- T cell infiltration in the kidney of LN patients, which was correlated with multiple clinicopathological features including estimated glomerular filtration rate (eGFR), proteinuria, the proportion of glomerulosclerosis and the degree of renal chronicity. In addition, a high level of IL-15 and IL15-expressing macrophage infiltration was detected in the periglomerular and intraglomerular tissues of LN patients, which enhanced the innate features, cytokine secretion and migratory capability of CD4 + CD28- T cells, and finally exerted direct TCR-independent cytotoxicity on glomerular endothelial cells in an IL-15-dependent manner in vitro.

Our study demonstrated that excessive IL-15 potentially promoted cytotoxic CD4 + CD28- T cell-mediated renal damage in LN. This finding may provide new insights into the potential association of premature aging and tissue damage in LN.