Collaborating Investigator: Ankur Singh
Affiliation: Cornell University

Funding Status: NIH R01AI132738
Project Period: 02/09/18-01/31/23

Summary

The goal of SP#5 is engineering designer organoids with tunable ligand specificities, understanding antigen specific immune response, and establishing a link between integrin ligand specificity and cell cycle epigenetics of germinal center reaction. NIM technologies from TR&D2 and metabolic reprogramming approaches from TR&D3 will be transferred (push) to Dr. Singh so that he can utilize these technologies to better achieve his immunoengineering goals in ways not possible w/commercial technologies.

Specific Aim 1. Engineer polyethylene glycol-based modular immune organoids with integrin specificities to determine the role of integrin signaling in controlling induction of GC phenotype and BCR signaling.

Specific Aim 2. Design modular immune organoids co-presenting soluble antigen and functionalized FAS ligand to facilitate the selective expansion, activation, and differentiation of antigen-specific B cell population in culture. A transgenic B1-8 mouse model will be used to study the effect of stimulating B cells with antigen and T cells will be incorporated in the organoids to enable antigen-specificity and selective enrichment.

Specific Aim 3. Establish a link between integrin ligand specificity and cell cycle epigenetics of GC reaction.

Approach

Humoral immunity against infections depends on the germinal center (GC) differentiation process in the B cell follicles of secondary lymphoid organs, such as spleen and lymph nodes. In GCs, B cells rapidly proliferate and somatically mutated high-affinity antibody secreting cells, i.e. plasma cells, are generated from naïve B cells in response to T cell-dependent antigen. To date, the scientific community have relied on animal models to generate high-affinity antibodies and discover fundamental knowledge of GC immunology. Yet we are far from understanding the extracellular and intracellular factors that contribute to the exuberant pace of the GC reaction and conversion to antibody secreting cells (ASCs). Our long-term goal is to develop a designer, biomaterials-based B cell follicle-mimicking microenvironment that recapitulates immune tissues.