|Germinal center (GC) B cells and T cells (blue) cluster within the B cell follicle (grey). GCs contain two distinct zones, known as the light zone and the dark zone, that cells move back and forth between. The light zone is identifiable by the presence of follicular dendritic cells (red), while the dark zone contains a dense network of CXCL12-expressing reticular cells (green). Movement of GC B cells between these zones is associated with switching between centrocyte and centroblast phenotypes.
|The GC dark zone is the principle site of somatic hypermutation and mitosis. Mitotic cells are identifiable by phospho-histone H3 staining (red). Zoomed images of the boxed cells are shown below. Selection is thought to occur in the light zone while cells are at the centrocyte stage.
|A simplified graphic model for GC responses. Our recent findings suggest that the switching of GC B cells between centroblast (dark zone) and centrocyte (light zone) stages is determined by an intrinsic cellular program involving a timer component. The transitioning between these stages prepares cells to engage in the processes associated with their respective zones.
Dr., Sir Henry Dale Fellow
The adaptive immune system learns from primary exposures to pathogens to help prevent secondary infections of the same or similar kinds. One of the key ways by which this is achieved is through the production of specific antibodies – secreted proteins, made by terminally differentiated B cells (plasma cells), that bind to foreign objects such as viruses and bacteria to prevent their infecting host cells and to promote their clearance from the body. Most effective vaccines depend upon antibodies for the protection that they confer, however the processes determining the quality of the antibodies generated during an immune response are incompletely understood. We are investigating the biology of antibody development.
Our main research interest is in determining the mechanisms controlling germinal center reactions. Germinal centers are unique transient structures that form within the B cell follicles of lymphoid tissues during immune responses and are the principle sites of antibody affinity maturation and B cell receptor diversification. Random point mutations are introduced into the immunoglobulin (antibody) genes of germinal center B cells for the purpose of refining their specificity for cognate antigen. Rare B cells in which mutations lead to increases in antibody affinity capture more antigen through their membrane receptors and present more peptide-MHCII on their surface, allowing them to out-compete neighboring cells in acquiring “help” from limiting numbers of follicular helper T cells. The quality of the “help” received is also likely to be reflective of the amount of peptide antigen presented. Affinity maturation occurs through many iterative rounds of mutation and selection. The benefits of affinity maturation are great enough to justify the risks associated with genome mutagenesis, however complex regulation of GC responses is needed because off-target mutations can and do cause lymphomas.
The switching of germinal center B cells between mutagenic (centroblast) and selection (centrocyte) stages is determined by an intrinsic cellular program involving a “timer”, however the molecular mechanisms controlling this behavior are not known and are a focus of our research. We also are invested in understanding the types of specialized adaptations that germinal center B cells have evolved to allow them to cope with the unique demands associated with frequently and repetitively changing receptor specificity while simultaneously ensuring that selection is stringent and efficient. We hope to gain a better understanding of the dynamics of the mutation and selection processes and to determine what signals contribute to them. Our approaches include developing new in vivo mouse models that allow us to interrogate the behavior of GC B cells in their native unperturbed environment. The medical value of this research is that it may lead to a better understanding of how to promote immunity, prevent autoimmunity and identify druggable targets for cancers.
Apoptotic cell fragments locally activate tingible body macrophages in the germinal center
Grootveld AK. et al, (2023), Cell
Secondary influenza challenge triggers resident memory B cell migration and rapid relocation to boost antibody secretion at infected sites
MacLean AJ. et al, (2022), Immunity
Hepcidin-Mediated Hypoferremia Disrupts Immune Responses to Vaccination and Infection
Frost JN. et al, (2021), Med, 2, 164 - 179.e12
Scoring a HAT-Trick against Lymphoma
Bannard O., (2019), Immunity, 51, 420 - 423
Germinal Center B Cells Replace Their Antigen Receptors in Dark Zones and Fail Light Zone Entry when Immunoglobulin Gene Mutations are Damaging.
Stewart I. et al, (2018), Immunity, 49, 477 - 489.e7