Germinal Center Biology
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.