Molecular regulation of NK cell functional maturation by the transcription factor BACH2

Natural killer (NK) cells are a specialised immune cell type that form a critical first line of defence against cancer and infection. NK cells recognise cancer cells and infections in a different way to CD8+ T cells. This makes them attractive as alternate targets for immunotherapy. Clinical responses to NK cell-targeted immunotherapies have thus far been modest identifying a need to better understand molecular processes that restrict their function. NK cells exist in a variety of different states, called functional maturation states. These have important implications for their ability to control infections and cancer. We lack an understanding of how NK cell functional maturation is regulated, though identifying such mechanisms may provide new therapeutic targets in NK cell-based immune therapies. In people, genetic variations in a gene that encodes a transcription factor protein called BACH2 are associated with susceptibility to multiple autoimmune and allergic diseases, caused when the immune system undergoes excessive activation. Recent experiments conducted in our laboratories indicate that BACH2 is expressed in NK cells and negatively regulates their functional maturation with consequences for tumour immunity. The purpose of this work is to establish the function of BACH2 in NK cells, testing the hypothesis that it is a critical negative regulator of NK cell functional maturation and testing its consequences for homeostasis and immune responses to infection and cancer. Our proposed study is organised into three aims: Firstly, we will find out how BACH2 affects the behaviour of NK cells under normal conditions, and during infection with influenza, where NK cells can contribute to both viral clearance and excessive inflammation. Secondly, we will examine the effect of BACH2 in NK cell responses against cancer, both in NK cells existing within the body, and upon therapeutic transfer into tumour-bearing hosts. Finally, we will examine the molecular processes that underpin the function of BACH2, finding out where BACH2 binds in NK cell genomes and which genes it regulates. Collectively, this research will enable a better understanding of how the function of the immune system is controlled to under normal conditions and during infections and cancer. This may enable development of new therapies that work by either restraining or enhancing immune responses in individuals with inflammation, infections and cancer.