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Elevated Expression of Transmembrane IL‐15 in Immune Cells Correlates with the Development of Murine Lupus: a Potential Target for Immunotherapy Against SLE

Presentation in trans by the Interleukin‐15 receptor α chain (IL‐15Rα) has been suggested as the main mechanism for IL‐15 anchoring to the cell surface, but it is also evident that IL‐15 can exist as a transmembrane protein. We herein demonstrate that replacement of the first 41 residues of human IL‐15 (hIL‐15) with Igκ chain leader sequence resulted in secretion of most of the recombinant hIL‐15 expressed in transfectant cells, thus identifying the transmembrane region of IL‐15. A fusion protein (hIL‐15Rα‐Fc) between the extracellular domain of hIL‐15Rα and the Fc fragment of IgG1 was prepared and shown to be able to bind with transmembrane IL‐15 (tmIL‐15). The level of tmIL‐15 expression in macrophages, activated T cells and B cells from 6‐month‐old BXSB male mice, an animal model for systemic lupus erythematosus (SLE), was significantly increased compared with that from BXSB females or young males. In addition, hIL‐15Rα‐Fc was able to block the T cell stimulating and anti‐apoptotic effect of the tmIL‐15‐positive BXSB macrophages in vitro. Intravenous administration of hIL‐15Rα‐Fc reduced the titre of autoantibodies against dsDNA and also proteinuria in aged BXSB males, implying that neutralization of IL‐15 activity in vivo may be an effective way of treating SLE.