Gene regulatory architecture of CD56 bright natural killer cells

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PROJECT SUMMARY This project focuses on how genomic regulators direct natural killer (NK) cells to control infections and malignancies. In this regard, the specific aims are: 1) to determine mechanisms by which circulating and tissue- resident “helper” like NK cells epigenetically remodel into each other; and, 2) identify regulatory transition points that “lock” circulating NK cells into their cytolytic lineage, blocking the helper identities. Natural killer cells are innate lymphocytes, which means they can recognize, and normally eliminate, infections and tumors before a full immune response needs to be generated. This innate functionality makes them particularly exploitable for a new generation of therapies: NK cells cannot participate in graft-versus-host disease (important for cellular therapy), they can be armed with antibodies (required for antibody-mediated therapies), and rapidly respond to their environment (important for cytokine therapies). Given their promise in novel anti- cancer and immune therapeutics, a deeper understanding of clinically beneficial NK cell phenotypes is of high priority. Unfortunately, chronic inflammation may prevent NK cells from functioning when exploited for therapies. As such, the goal of this proposal is to define how inflammatory environments establish NK cell identities, via epigenetic programming. First, We will investigate how chronic inflammation alters the NK cell epigenome, shutting down the beneficial features of NK cells used in therapy. We will then assay NK cell heterogeneity during inflammation, including their epigenetic landscape. The output will be made available as publicly available datasets, ideally used by many researchers to identify mechanisms governing killer NK cell identities. Indeed, as this process may be dysfunctional in diverse pathologies, the data could be of interest to a wide range of fields. Many infections, solid tumors and hematological malignancies, such as acute myeloid leukemia, create environments that reprogram NK cells. Thus, the identified pathways may be a major barrier to effective immunity.