BATF as an inducible regulator of natural killer cell expansion and effector function

Project Summary: Natural killer (NK) cells exist in a chronically “primed” state that facilitates rapid cytokine production, chemokine-mediated dendritic cell and macrophage recruitment, and direct target elimination. These cells play a pivotal role in protection against -herpesviruses and coronaviruses, and in the immune response against metastatic tumors and leukemia. Emerging evidence supports an important role for NK cells in the initiation of the immune response against some solid tumors. While NK cell survival and function can be suppressed in the tumor microenvironment, these cells can be restored by environmental manipulation or checkpoint blockade therapy. These findings raise the possibility that NK cells, if manipulated appropriately, could have therapeutic benefits in multiple disease contexts including in solid tumors. Therefore, a comprehensive understanding of the mechanisms controlling NK cell survival, proliferation, and effector function in different disease contexts is needed. In this grant, we present preliminary data identifying BATF as a transcription factor induced by the proinflammatory cytokine IL-12, which is responsible for the priming of NK cells during their development and for NK cell expansion in response to viral infection. We will test the consequences of altered BATF expression, both loss and gain of function, on NK cell maturation and anti-tumor immunity (Aim 1) and the NK cell response to viral infection (Aim 2). We propose a comprehensive characterization of BATF target genes and the impact of BATF on chromatin accessibility, histone modification, and functional output. Taken together, these studies will provide a broad view of the requirements for BATF and the potential for modulating BATF or its target genes for therapeutic intervention in anti-viral and anti-tumor immune responses.