Interleukin-2 activated microglia engulf tumor infiltrating T cells in the central nervous system

Interleukin-2 (IL-2) has been utilized to treat cancer patient. However, recent studies disclosed that IL-2 induces T cell death. To clarify IL-2 induced T cell apoptosis at tumor sites in the central nervous system (CNS), we utilized an intracranial implantation of IL-2 cDNA transduced murine tumor cells and examined freshly recovered tumor infiltrating T lymphocytes (TIL) with a magnetic beads separation method. CD8+ TIL recovered from the IL-2 therapy model had three times more apoptosis than a control group, tumor weights at day 12 decreased (0.016 versus 0.041 g/mouse) and the number of TIL per gram of tumor tissue increase more than six times by IL-2 therapy (5.69x106 versus 33.7x107 cells per mouse). In addition, both activation marker expressions (CD25 and CD69) and cytokine message levels (interferon γ, and tumor necrosis factor α) on CD8+ TIL decrease in the IL-2 therapy model. Moreover, we detected higher CD8β message levels in purified tumors associated with F4/80+ cells from the IL-2 model than the control by a one-step RT-PCR method. Finally, we observed many CD8β+ TIL surrounded by numerous infiltrating F4/80+ cells in the tumor tissues of the IL-2 therapy model by immuno-fluorescence microscopic analysis. Our data show that IL-2 sensitization of apoptosis induction for CD8+ TIL occurred and the apoptotic T cells were eliminated by F4/80+ microglia in the CNS. Moreover, this is the first report describing in situ elimination of TIL by F4/80+ phagocytic cells in the CNS.