Intestinal Programming of Gut-Associated Germinal Centers

About This Grant

PROJECT SUMMARY In the healthy intestine, the microbiota and intestinal immune system are intimately linked. One of the major regulators of the microbiome is the mucosal antibody, IgA, produced by intestinal B cells, which exerts unique immunomodulatory functions on bacterial communities. Failures in bacterial regulation by IgA has serious health implications, impacting the progression of a wide range of diseases like inflammatory bowel disease (IBD), obesity, cancer, and depression. However, whilst many studies have identified roles for IgA in bacterial regulation, how the presence of the microbiota directs differential programming of local B cell responses towards production of regulatory IgA is poorly understood. Most homeostatic IgA is produced via gut-associated germinal centers (gGCs), microanatomical niches which are essential for B cell and antibody evolution. Although we have previously shown that gGCs support effective selection of microbiota-specific B cell clones, accumulating evidence indicates that fundamentally altered signaling networks govern the dynamics of steady-state gGCs. In our preliminary data we identify composition of the microbiota as a significant modulator of several aspects of gGC responses, suggesting a crosstalk that is established between the intestine, B cells, and the microbiota. We therefore hypothesize that ‘education’ in the intestinal microenvironment by the microbiome fundamentally alters how B cells to evolve in gGCs. We show evidence that the responsiveness of several immunoreceptors is modified following exposure to the microbiome, suggesting that chronic bacterial stimulation broadly desensitizes receptor function and sets lowered activation thresholds. Commensals are perceived by cells specifically through the B cell receptor (BCR) and via generic sensing through Toll-like receptors (TLRs). We present new evidence supporting that sustained stimulation by TLR ligands acts as a signal rheostat, tuning inherent responsiveness of B cell receptor and CD40 signaling networks to regulate permissive entry to chronic gGCs. Consequentially, TLR deficient animals host enlarged gGCs, in direct opposition to inflammation-driven GCs, which are severely compromised in the absence of TLR activation. We propose a model whereby continuous low-level TLR signaling in combination with weak BCR binding could be sufficient to initiate gGCs towards the microbiome, facilitating the selection of a regulatory pool of IgA with broad binding specificity. We will test our hypotheses through use of two specialized imaging approaches, a novel commensal-specific transgenic BCR mouse model, and restricted-diversity microbiomes, to address how exposure to microbial signals tunes the magnitude and specificity of intestinal B cell responses. Our studies will further our understanding of the mechanisms driving dysregulation of the microbiome, important for autoimmunity, cancer, and metabolic disorders. Results from our proposal will also generate valuable insights into the rules governing tissue-specific antibody responses and IgA memory, a rapidly emerging interest area in mucosal infectious disease research.