Date of Graduation
School of Medicine
Our research determined that the epithelial master transcription factor Grainyhead-like 2 (GRHL2) promotes sensitivity to Natural Killer (NK) cell-mediated killing, and modulates the interferon I (IFN-I) response of epithelial cells. Immune surveillance by NK cells constitutes a major selective pressure for circulating tumor cells. Epithelial (GRHL2-expressing) cells exhibited significantly higher rates of NK conjugation, a crucial step in direct cell-mediated cytotoxicity. Mechanistically, GRHL2 upregulates expression of intercellular adhesion molecule 1 (ICAM-1), a cell surface molecule critical for NK to target cell synaptogenesis. GRHL2 epigenetically regulates gene expression, and we found that GRHL2 mutant proteins unable to interact with the epigenetic modifiers p300 or KMT2C/D exhibited altered NK sensitivity, and ICAM-1 expression was lost. In summary, the epithelial state, enforced by GRHL2, kept these cells susceptible to NK-mediated cytolysis. Further, our data suggest GRHL2 critically promotes IFN I production in response to a double strand RNA mimetic. The results from these experiments identify novel roles for GRHL2 in maintaining the relationship between epithelial cells and the innate and adaptive arms of the immune system.
MacFawn, Ian Philip, "Grainyhead-like 2 Sensitizes Cells to Natural Killer Cell Cytotoxicity and Promotes the Interferon Response" (2020). Graduate Theses, Dissertations, and Problem Reports. 7778.