Dimeric IL-2 induces necrosis of Interleukin-2 receptor positive cells (CCR6P.217)

Abstract Mice deficient in T regulatory cells (T regs) die from systemic inflammation. Breeding these mice with IL-2KO mice clears inflammation in lungs and skin, suggesting that IL-2 has pro-inflammatory functions beyond promoting survival of T regs. We recently identified a dimeric form of IL2 mammalian tissues that is cytotoxic to cells expressing IL-2 receptor (IL-2R), which provides an explanation for the above. Exposure of IL-2R+ cells to dimeric IL-2 results in rapid release of LDH. We hypothesized that dimer-mediated cell death is consistent with the characteristics of necrosis. To test this hypothesis, we exposed Jurkat cells to dimeric IL-2 and processed them for electron microscopy at 5 minutes. EM revealed swollen nuclear membranes and mitochondria consistent with early necrosis. Exposure of vascular smooth muscle cells (VSMC) to dimeric IL-2 induced 50% loss of cellular ATP at 5 minutes and nearly complete loss at 20 minutes. Using the mitochondrial membrane potential indicator JC-1 in VSMC, nearly all mitochondria lost their MMP by 10 minutes. These data indicate that dimeric IL-2 kills cells by necrosis. Our finding that dimeric IL-2 is cytotoxic to cells expressing IL-2R, lymphoid or non-lymphoid, has implications beyond the immune system. These studies combined with prior studies showing presence of matrix-bound IL-2 in arteries, suggests dimeric IL-2 may contribute to vascular inflammation in processes such as atherosclerosis.