Transcriptional regulation of innate αβ CD8+ T cell development in Itk deficient mice (36.35)

Abstract

Abstract Inducible T cell kinase (Itk) deficient mice develop a large population of αβ CD8+ innate-like T cells that possess a memory-like phenotype and are dependent on IL-15. Similar to other innate T cell lineages, these cells are positively selected by hematopoietic cells instead of thymic stroma in a SAP dependent manner that involves the interaction of signaling activation molecule (SLAM) family members. While much work has been done to characterize these cells, very little is known about the molecular pathways that prevent (Wt) or initiate (Itk-/-) the expansion of innate CD8+ T cells. One clue came from work examining mice with a T-cell specific deletion of CREB binding protein (CBP) driven from the Lck proximal promoter. These mice revealed a similar expansion of CD8 T cells with an innate phenotype. CBP is a transcriptional co-activator, which possesses histone acetyl transferase (HAT) activity and is known to associate with a wide range of transcription factors, most notably the cAMP response element binding protein (CREB). We find that TCR stimulation induces robust phosphorylation of CREB that is impaired in Itk-deficient T cells. We are currently further evaluating how Itk-deficiency affects CREB/CBP activation, and the impact of these pathways on transcriptional programs leading to innate T cell development.