Autoimmunity research: We are using genetically modified mouse models to address the roles of specific cell types (e.g. B cells, T cells and DCs) in systemic autoimmunity. Currently we are particularly interested in the identity and function of autoreactive T cells that help autoreactive B cells and that infiltrate target tissues using novel TCR cloning methods. A second major area is investigating the regulatory role of TLR9 and stimulatory role of TLR7 in lupus, and to define how TLRs function in tissue-specific fashion. To this end we have made conditional alleles of both TLR7 and TLR9 on a lupus-prone mouse genetic background and we are dissecting the tissue-specific roles of these receptors. We have also introduced key point mutants and chimeric molecules into the germline of this mouse strain to test hypothesis about function in vivo and in signaling assays in vitro. Finally, we continue to work on the role of B cells in lupus and how best to therapeutically target them.
B cell immunity: we are investigating the mechanisms of cellular selection and differentiation in the germinal center (GC), a site of rapid proliferation, mutation, and differentiation into memory B cells (MBC). We recently showed that the GC shifts its output from MBC to plasma cells as it matures with time. We are actively working on “non-canonical” extrafollicular B cell responses, which induce isotype switch and mutation outside of GC as well as generate MBC; a key question is what controls the choice between these two types of response. We have also identified novel subsets of MBC in mice and are studying their origins and function using epigenetic, single cell, and subpopulation gene expression analysis. Our work on MBC has now been extended to humans, where, by studying multiple lymphoid and mucosal tissues, we have identified novel populations of MBC.