Nicholas Pease, PhD, Postdoctoral Fellow University of Pittsburgh To generate immediate and long-term humoral immunity, activated B cells undergo a bifurcation into short-lived antibody-secreting plasmablasts and long-lived plasma cells (LLPC). The latter cells are generated via T cell help in germinal centers (GC) after a process of affinity maturation and consequently secrete high-affinity antibodies. To more rationally design vaccines and immunotherapies, there needs to be a quantitative and deep understanding of molecular mechanisms that control the B cell bifurcation in humans. Dr. Pease proposes to couple two in vitro approaches that recapitulate human B cell activation and functional bifurcation dynamics to elucidate the molecular mechanisms that control the quality and magnitude of the humoral immune response. In Aim 1, he will delineate the T cell derived signals that modulate human B cell fate bifurcation and then perform single cell lineage fate mapping to identify GC B cell precursors which are critical to generating durable, high-affinity LLPCs but have remained elusive. In Aim 2, he will use trimodal single-cell profiling, computational modeling, and combinatorial CRISPR-Cas9 perturbations to generate a comprehensive model of B cell signaling-coupled transcription factor networks that regulate human B cell fate bifurcation. He anticipates that this work will uncover the regulatory apparatus that controls the quality and magnitude of humoral immunity and will provide a foundational systems immunology approach to study the fundamental causal mechanisms underlying the state of a patient’s humoral immune response. Such a foundational experimental and conceptual framework could be used to design more rational and precise patient-specific vaccination and immunotherapy strategies. Projects and Grants Multimodal single cell analysis of signaling-coupled transcription factor networks regulating human B cell fate decisions University of Pittsburgh | All Cancers | 2022 | Harinder Singh, Ph.D.
