GERMINAL CENTER MECHANICS
Our work in this area focuses on germinal centers as "evolution machines" that take as an input low-affinity B cells and output high-affinity ones. How does this evolutionary process work? At the cellular level, how do B cells "know" when they make higher affinity antibodies than their neighbors? How much of this is intrinsic to the B cell, and how much depends on other cells like T follicular helpers? We use a combination of mouse genetics, immunoglobulin sequencing, and two-photon imaging to tackle these questions, which have implications to our understanding of antibody affinity maturation and B cell lymphomagenesis.
In addition to generating high-affinity antibodies by affinity maturation, germinal centers and other steps in the B cell selection processes can also play the role of "filters" that narrow an initially wide diversity of responding B cell clones into the more focused pool of clones that secrete antibody into serum. We study how competition between B cell clones shapes the resulting antibody pool in different settings, ranging from vaccination and viral infection to the response to bacterial commensals in the gut. We hope to contribute to the understanding of vaccine-relevant phenomena such as immunodominance, antibody imprinting, and "original antigenic sin," as well as of the homeostatic B cell response in the gut.
Our most current model of germinal center selection proposes that higher affinity B cells can retrieve and present more antigen to germinal center-resident T follicular helper (Tfh) cells, which then drive B cell proliferation. This places special emphasis on the dynamics of the Tfh cells themselves as a driving force in the germinal center. We study different aspects of Tfh biology, including their clonal and migratory dynamics and their cellular and molecular biology.
We developed LIPSTIC (Labeling of Immune Partnerships by SorTagging Intercellular Contacts), a method to study cell-cell interactions in vivo based on enzymatic transfer of labeled substrates from one cell to another. Just like actual lipstick, our system allows us to to track cellular kiss-and-run events. We apply LIPSTIC and its variants to contact-trace immune and non-immune cells in various mouse models, from germinal center selection to oral tolerance and cancer immunology.