I have recently found that a key TF, BACH2, functions as a pervasive negative regulator of immune activation, promoting formation of Treg cells while suppressing the differentiation and function of multiple Teff lineages. I aim to extend our understanding of this newly identified molecular pathway. Key goals: 1. To determine how extrinsic signals regulate BACH2 to enable responses to infection. Phosphorylation of BACH2 at S520 causes its functional inactivation. I propose to: a. Determine how extrinsic signals cause BACH2 phosphorylation b. Determine how phosphorylation inactivates BACH2 c. Generate phospho-mutant S520A mice and characterise immune responses to infection 2. To examine the function of BACH2 within Treg cells. BACH2 interacts with the lineage-specifying TF Foxp3. I propose to: a. Measure genome-wide function of BACH2-Foxp3 complexes b. Establish domain- and sequence-level determinants of BACH2-Foxp3 interactions c. Determine how Treg-intrinsic BACH2 regulates homeostasis and tumour immunosuppression 3. To determine mechanisms of gene regulation at distal enhancers. BACH2 binds distal enhancers and interacts with chromatin modifying complexes. I propose to: a. Determine how BACH2 regulates chromatin states at enhancers b. Determine whether BACH2 regulates higher-order chromatin structure c. Determine how BACH2 mediates context-dependent regulation of gene expression