Comparative genome-wide screens reveal novel regulators of Cytotoxic Lymphocyte-mediated cell death.

Abstract

Abstract Cytotoxic Lymphocytes (CLs) are key players in the effector branch of the immune response, detecting and eliminating transformed and pathogen-infected cells. While the physiological roles of CL-mediated apoptosis are well established, many regulators of these apoptotic pathways in target cells remain poorly understood. We performed comparative genome-wide haploid genetic screens in a human cell culture model for CL killing and resistance in order to identify positive and negative regulators of target cell survival during CL-mediated killing. These regulators include genes encoding glycosylphosphatidylinositol (GPI) anchor synthesis enzymes and immune surveillance receptors. In order to identify further potential components of these pathways, we performed an additional resistance screen in a GPI-anchored protein deficient haploid cell line. We identified both common and disparate regulators between unaltered target cells and GPI-anchored protein deficient target cells. These disparate regulators underline the importance of GPI-anchored proteins in CL target recognition and killing. Some gene knockouts enriched by CL-mediated killing in both screens are also mutated in cancer. Further study of the regulators identified by these screens will advance our understanding of how the many killing pathways used by CLs shape the interaction between the immune system and cancer.