Engineered ImmuneChip Platform to Study B cell Migration and Affinity Maturation

项目总结

PROJECT SUMMARY Developing vaccines against emerging infections such as SARS-COV-2 and influenza requires an enhanced understanding of the underlying antibody immune response in the body. Although antibodies, used as therapeutic agents, can be derived from fused hybridoma models, animal models, or genetic engineering, these techniques cannot explain the detailed immunological process of antibody formation and therefore, cannot decipher or predict outcomes of host-pathogen interactions. The study of the mammalian immune system has long been limited to in vivo approaches or single time point studies with limited donor lymphoid tissues, which often do not allow multidimensional spatial and temporal control of intracellular and extracellular processes that regulate the decisions of immune cells. This is attributable to the complexity of lymph nodes, which have distinct niches of B and T cells, stromal cells, and antigen-presenting cells. When exposed to antigens, B cells undergo a highly controlled activation process, called the germinal center (GC) reaction, which makes antigen-specific antibody-secreting cells. Inside GCs, naïve B cells become activated, proliferate, migrate, undergo immunoglobulin class switching, and increase their antigen affinity by somatic hypermutation and T cell-based selection, yielding long-lived plasma cell with high affinity for specific antigens. However, the mechanistic understanding of the GC process is largely derived from mouse lymph nodes or 2D B cell cultures, that do not generate a bona fide GC response. The goal of this R21 is to develop an ImmuneChip platform that (A) incorporates key molecular and cellular components of the lymph nodes to induce GC reactions and enable B cell migration, (B) selects for high-affinity B cells through a forced affinity maturation process. The ImmuneChip will provide multidimensional control of cellular processes in GCs, allow rapid generation of immune therapeutics, and serve as a rapid testing platform to identify candidate vaccines and immunogens. The successful application of this project will facilitate the rapid discovery of vaccine candidates for existing and emerging infections, including lethal influenza and SARS-CoV-2.