Myeloid derived suppressor cell function is potentiated by interleukin 15 in vitro 4645

Abstract Description Myeloid derived suppressor cells (MDSCs) dampen immune responses by inhibiting natural killer (NK) and T cells. As previous studies suggest that MDSCs can express interleukin 15 (IL15) receptor alpha, we sought to evaluate the effects of IL15 on MDSC function in vitro. We isolated CD33+ cells from human peripheral blood mononuclear cells (PBMCs) and cultured them with IL6 + GM-CSF ± IL15 to generate MDSCs. Matched donor PBMCs were stimulated with anti-CD3:CD28 + IL2 and cultured with MDSCs to assess suppressive function. NK and T cell phenotype and function were evaluated by flow cytometry. At responder:suppressor ratios of 2:1, MDSCs significantly inhibited proliferation of NK, CD4, and CD8 T cells assessed by Ki67. MDSCs significantly reduced CD69 expression on NK cells and Granzyme B in NK, CD4, and CD8 T cells. MDSCs cultured with IL15 during the 7-day expansion process demonstrated significantly greater suppression of NK, CD4, and CD8 T cell proliferation, NK cell CD69, and NK, CD4, and CD8 T cell Granzyme B. Greater differences in the measured IL15 suppressive effects were detected in NK cells compared to T cells. Overall, IL15 pre-conditioning in vitro lead to augmented suppressive effects of MDSCs on NK and T cell proliferation and activation, with greater effects on NK cells. As IL15 is a critical cytokine for NK cell persistence and proliferation, better characterization of IL15 effects on MDSC function is likely to have translational impact on therapeutic strategies. Funding Sources NIH Grant 1T32CA251007 University of California Davis Flow Cytometry Shared Resource Laboratory with funding from the NCI P30 CA093373 Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)