A Deep Dive into Humoral Immunity
During humoral response, germinal centers selectively mutate antigen specific B cell receptors towards high affinity antibodies.
We aim to understand factors that modulate affinity maturation and create tools to monitor its progress.
Cancer immunotherapies direct the body's own immune system to eliminate cancer cells.
Current strategies primarily rely on mobilizing T cells. We seek to expand the role of B cells in anti-tumor responses.
While animal models provide great immunological insights, the translatability of these findings to humans is untested.
We intend to create clinically relevant immune system models for basic and translational research.
Germinal Center Progression
After vaccination, antigen specific B cells differentiate into several different fates. In particular, germinal center (GC) B cells reside within the follicle where they interact with T cells, antigens presented by follicular dendritic cells (FDC), and other stromal populations. Within the GC, B cells compete for pre-existing antigen and survival cues while mutating the B cell receptors (BCRs) towards higher affinity counterparts.
We will investigate the roles of long term antigen availability and stability on GC progression. Flow and imaging based FRET analysis along with immunological techniques will be used to characterize and perturb this process in vivo. In addition, we will also develop approaches to monitor the affinity maturation process.
FDC captured antigen
14 days after immunization
FRET imaging for antigen integrity within tissue section
Adoptive transfer as an investigative tool
KP Tumor within Mouse Lung
alpha smooth muscle actin
Courtesy of Dr. Laura Maiorino
B cells in Anti-cancer Response
Cancer immunotherapies employ several distinct approaches such as adoptive cell transfers, checkpoint blockades, or peptide vaccines and are often administered in combinations. Amongst these approaches, T cells play a central role in targeting and eliminating tumor cells although a few strategies have focused on innate immune cells. However, recent findings suggests that B cells can also play critical roles in immunotherapies although their function is not yet fully understood.
We aim to develop approaches to incorporate B cells into anti-tumor responses. These projects will interface approaches and knowledge from cancer therapies, B cell biology, and protein engineering.
GC B cell interactions
In vitro cultures
Time lapse of human lymphoid tissue in chip after 3 days of culture
Red: T cells Blue: B cells Green: Antigen
Fluidic system to culture lymphoid tissues ex vivo
Animal models have provided tremendous insights into immunology, yet to what degree these findings translate to humans is not fully understood. Nonetheless, our understanding of germinal centers have been predominantly based on mouse models with limited understanding of cell-cell interactions and affinity maturation that occur in human lymphoid tissues.
Thus, we will work towards recapitulating human germinal centers in vitro and develop biological tools to delineate the role of T cell help and antigen induced signaling on GC B cell progression. Moreover, we aim to engineer fluidics based microenvironments conducive for GC progression. Beyond fundamental research, we strive to discover novel antibody based therapeutics with these systems.