Research

The overall focus of the Pipkin lab is to elucidate how chromatin structure and transcription controls the gene expression programs that establish and maintain the differentiated states of T cells. The lab specifically studies how naïve CD8 T cells differentiate into effector and memory cytotoxic T lymphocytes (CTL). CTL are killer lymphocytes that hold outstanding promise for controlling viral infections and cancer therapeutically, as they can be employed in adoptive immunotherapy and are the target of successful vaccination.

Novel Approaches

The Pipkin lab has developed novel approaches to map the fundamental repeating structures of chromatin (nucleosomes) at unprecedented resolution, novel reporter genes to track cells in vivo that induce expression of Prf1, an essential gene that is required for the anti-tumor killing activity of CTL, and the first systems to conduct genome-scale in vivo pooled RNA interference (RNAi) screens in T cells during the course of viral infections. Using these tools and approaches, the Pipkin lab is clarifying how transcription factors govern the specific organization of nucleosomes that enforces CTL differentiation, identifying the chromatin regulatory factors that maintain the differentiated state “epigenetically”, and demonstrating how these processes mediate durable immunity.

Current Projects

Transcriptional Regulation of Antiviral Response & Memory T Cell Formation

Graphic illustration of transcription factors.

CD8⁺ T cell memory formation is essential for antiviral immunity. Development of memory CTLs rely on transcription regulation by transcription factors (TFs). However, of the thousands of TFs expressed in T cells, very few are known to contribute to memory formation; and for the ones that are known to contribute to CTL memory formation, the mechanism of transcription control is unexplained. We are interested in identifying TFs that contribute to the development of memory CD8⁺ T cells using in vivo loss-of-function screens that employ RNAi and CRISPR-guided screens and bioinformatics approaches.

Tumor CTL Response & Immunotherapy

We aim to characterize how the immune system shapes and defines responses to viral infections and malignancies. By combining gene expression analyses and bioinformatic tools, we are addressing how differential patterns of gene expression in both CD8+ T cells and tumor cells result in distinct, clinically relevant phenotypes. In addition, we are using shRNAmir libraries focused on cell surface molecules to conduct loss-of-function screens in both T cells and tumor cells, and are defining which receptors regulate T cell mediated tumor clearance and T cell exhaustion in vivo. We are also using novel human PRF1 BAC-transgenic mice to define specific subsets of activated CD8+ T cells that differentiate into bona fide CTL during immune responses in vivo.