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Natural killer (NK) cells are critical to immune surveillance against infections and cancer. Their role in immune surveillance requires that NK cells are present within tissues in a quiescent state. The functional maturation of NK cells is a tightly regulated process which is controlled by transcription factors (TFs), and multiple positive regulators of this process have been defined. However, mechanisms by which NK cells remain quiescent in tissues are incompletely elucidated. The transcriptional repressor BACH2 plays a critical role within the adaptive immune system but its function within innate lymphocytes has been unclear. The studies presented here show that BACH2 acts as an intrinsic negative regulator of NK cell maturation and function. BACH2 is expressed within developing and mature NK cells and promotes the maintenance of immature NK cells by restricting their maturation in the presence of tonic IL-15 signalling. Loss of BACH2 within NK cells results in accumulation of activated NK cells with unrestrained cytotoxic function and increased immune surveillance to pulmonary cancer metastasis. These findings establish a critical function of BACH2 as a negative regulator of innate cytotoxic function and tumour immune surveillance by NK cells.

T cells coordinate immune functions by differentiating into highly specialised cellular lineages that either promote or suppress immune reactions. Whereas effector T (Teff) cells drive immune activation and promote clearance of infections and cancer, regulatory T (Treg) cells suppress their function to prevent excessive immune reactions that would otherwise result in autoimmune and allergic disease. During cell fate decisions, access to lineage-specific regulatory elements in the genome, which is tightly controlled by chromatin structure, is required to acquire a specific gene expression profile and a new cell identity. The dynamic changes of the chromatin landscape during Treg differentiation are largely unknown. To study this, I measured chromatin accessibility during the activation of naïve CD4 + T cells in the presence of TGF β (iTreg) or no cytokine (Th0) at different time points and integrated them with known gene expression and histone modification datasets to further characterise these changes. This shows that the chromatin landscape in iTreg cells undergoes dynamic remodelling in response to TCR stimulation and cytokine signalling with convergent effects of the two signals at many regulated loci. BACH2 is a transcriptional repressor whose expression is predominantly restricted to lymphocytes. Whether the suppression role of BACH2 is mainly through steric competition with the AP-1 family or involves other mechanisms is currently unclear. To test this, I measured gene-wide accessibility, DNA binding, and gene expression in Bach2-deficient and Bach2-sufficient Treg cells. While BACH2 is a critical regulator of T cell differentiation, its effect on accessible chromatin was minimal supporting a model whereby it functions principally as a steric repressor of AP-1-driven gene expression. Prior to Treg lineage commitment, BACH2 expression is required for induction of Foxp3, but its role after Treg lineage commitment has been unclear. To test this, I examined gene expression and genome-wide chromatin accessibility in natural Treg (nTreg) cells. This shows that BACH2 is repurposed following Treg lineage commitment, and represses the induction of activated Treg genes to promote the quiescence of resting Treg cells.

Regulatory T (Treg) cells are central to the maintenance of immune homeostasis and their dysfunction underlies the pathology of numerous diseases. Treg cell populations are phenotypically heterogeneous, comprising functionally quiescent resting Treg (rTreg) cells, which upon antigen stimulation, differentiate into functionally activated Treg (aTreg) cells. The purpose of rTreg cell populations and how their naïve-like phenotype is maintained despite chronic exposure to cognate self- and foreign antigens remains to be understood. The transcription factor BACH2 is critical for early Treg cell lineage specification, however, its function following Treg lineage-commitment is unresolved. The studies detailed herein demonstrate that Bach2 is highly expressed during Treg cell development in the thymus. High levels of Bach2 are maintained in post-thymic, lineage-committed rTreg cells but is downregulated in aTreg cells, and upon inflammation. Functionally, BACH2 acts to restrain T cell receptor (TCR)-driven activation in rTreg cells and constrain their differentiation into aTreg cells. Cell-autonomous expression of BACH2 is required following Treg cell lineage-commitment for functional quiescence and long-term maintenance of Treg cell populations. This is necessary for the restraint of excessive memory differentiation and IFN-γ production by CD8+ T cells. Therefore, in lineage-committed Treg cells, BACH2-mediated restraint of aTreg cell differentiation is required for the maintenance of immune homeostasis. These findings deepen our understanding of Treg cell biology and extend our knowledge of the function of the transcription factor BACH2 in lymphocytes.