Bei Liu, M.D., MPH

Associate Professor
Department: Microbiology & Immunology
Programs: Inflammation, End Organ Disease

 

 

Research Interests:

The intestinal immune system is responsible for balancing immunity and tolerance. Among professional antigen-presenting cells (APCs), dendritic cells (DCs) are known to orchestrate both innate and adaptive immunity. In the intestine, DCs are strategically positioned to protect the gut while maintaining mucosal tolerance against food, self-antigens and microbiota. DCs recognize and respond to microbiota through multiple pattern recognition receptors, including TLRs and NLRs. How DCs maintain mucosal homeostasis and what are the precise roles of gut microbiota in the process remain incompletely understood. Answers to these questions hold the key to generating novel therapies against many human diseases including inflammatory bowel diseases (IBD).

Dr. Liu’s laboratory has long been interested in the study of grp94 (also known as gp96) which is an essential immune chaperone for TLRs, integrins and other vital innate receptors. The important client network of grp94 creates a unique opportunity for us to unmask the roles of multiple receptors on APCs simultaneously by genetically manipulating only one molecule. Dr. Liu’s laboratory has generated several lineage-specific grp94 KO mice to delineate the contribution of grp94 and its clientele in host defense. They have found that deletion of grp94 from DCs results in alteration of DC and regulatory T cells (Tregs) in the colonic lamina propria, loss of oral tolerance, and high susceptibility to chemical-induced colitis. Surprisingly, DC- but not macrophage- or B cell-specific grp94 KO mice develop spontaneous colitis at 24 weeks of age and demonstrate dramatically increased systemic bacteria-specific IgA as well as fecal IgA. Intriguingly, such a genetic maneuver causes a profound alteration of the gut microbiota and significant colonization of the colon (up to 50% of the colonic bacterial species) with a mucin-degrading commensal bacterium, Akkermansia muciniphila, whose role in the gut mucosa has not been well explored. Moreover, a recent study showed that loss of grp94 in gut APCs was strongly associated with Crohn’s diseases. Currently, Dr. Liu’s research is focused on: (1) determining the impact of grp94 loss in DCs on T cell polarization and tolerance using a novel T cell receptor (TCR) transgenic mouse against antigens from segmented filamentous bacteria (SFB); (2) determining if selective KO of grp94 in different DC subsets influences gut immunity differently; (3) determining the grp94-specific client network in DCs; (4) defining the roles of specific commensal bacteria including Akkermansia muciniphila (A. muciniphila) in regulating colitis by colonizing mice in germ-free conditions; (5) determining the human IBD-associated microbiota using a unique germ-free DC-grp94 KO mouse model.

Dr. Liu’s laboratory also studies extrinsic and intrinsic factors regulating commensal-specific T helper-17 cells. Previous studies showed that Th17 cells have unique antigen specificity among gut CD4 T cell compartments. Intriguingly, the majority of naturally arising Th17 cells are specific for antigens uniquely found in segmented filamentous bacterium (SFB). The mucosal CD4 T cell differentiation is not stochastic, but follows a deterministic path whereby the fate of antigen-specific T cells is directed by the bacterial contexts of cognate antigens. The focus of this project is to carry out rigorous genetic studies to determine the role of cytokines in mucosal Th17 cell development, and determine a specific DC subset responsible for presenting SFB-derived antigens.

Publications:

PubMed Collection