Orchestration of PI3K-dependent transcriptional programmes by the transcription factor BACH2

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CD8+ T cells powerfully coordinate immune responses against intracellular infections and cancer. During immune responses, CD8+ T cells proliferate and differentiate into effector cells that promote elimination of target cells. Effector cells are short-lived and this enables restoration of normal immune function upon resolution of infection. However, a fraction of cells escape this fate and persist to form long-lived memory cells. Memory cells provide a durable self-renewing source of target-specific cells and can persist for decades following infection to generate more efficient secondary responses upon reinfection. CD8+ T cells also become terminally differentiated or exhausted in response to chronic infections and cancer and this impairs their function. Our previous work has identified a key molecular pathway, termed the phosphoinositide 3-kinase (PI3K) pathway, that powerfully regulates CD8+ T cell differentiation. Activation of the PI3K pathway drives widespread changes in gene expression to promote effector differentiation and prevent the formation of memory cells. Mechanisms by which the PI3K pathway causes changes in gene expression are not fully understood. In this study, we will investigate how the PI3K pathway controls the function of a class of proteins called transcription factors (TFs). TFs bind to regulatory regions within DNA and modulate gene expression to control cellular differentiation. We have recently found that the PI3K pathway controls the function of a transcription factor, BACH2, through a process called phosphorylation. We will investigate this new molecular axis, determining how the PI3K pathway regulates the function of BACH2 to control CD8+ T cell responses. Our experimental approach is divided into three components: 1) We will determine the function of BACH2 in regulating CD8+ T cell responses to infection. To do this, we will use a mouse model in which BACH2 is specifically deleted in CD8+ T cells and study immune responses following infection with experimental pathogens. 2) We will determine how the PI3K pathway controls the function of BACH2 to regulate immune responses to infection using a new mouse model in which BACH2 cannot be phosphorylated. We will also determine how BACH2 phosphorylation regulates BACH2 function at a molecular level. 3) We will test the contribution of BACH2 to PI3K-mediated transcriptional programmes in CD8+ T cells. To achieve this, we will utilise mouse genetics to specifically manipulate the PI3K pathway, and regulated transcription factors in CD8+ T cells, measuring consequences of these experimental manipulations on global gene expression and corresponding this data with analyses of transcription factor binding throughout the genome. This work will extend our understanding of how the PI3K pathway exerts such pervasive control over CD8+ T cell differentiation and provide insights into how external cues control gene expression to shape the outcome of immune responses. This will provide targets for development of new vaccine approaches and immune-based therapies for chronic infections and cancer.