Different roles of fetal- and adult-derived IgA secreting cells against GI infection

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Abstract IgA is the most abundant immunoglobulin produced in the lamina propria (LP) of the intestine and protects the host against microbial invasions into intestinal mucosa by coating and excluding them. Selective IgA deficiency is the most common immunodeficiency, and more than 50% of patients are asymptomatic. However, other patients develop various diseases such as inflammatory bowel diseases, allergies, autoimmune diseases, and recurrent infections. Despite the essential roles of IgA, it still remains unknown what causes the different clinical manifestations of this disease. One of the barriers to understanding the pathology of selective IgA deficiency is a gap of knowledge about the heterogeneity of developmental origin of the IgA-secreting cells. Our long-term goal is to fill this knowledge gap and to determine the roles of IgA+ cells of different origins in the mucosal immunity. There are two known pathways in producing IgA secreting cells: T-cell independent (TI) and T-cell dependent (TD) pathways. TI-IgA is a low-affinity polyclonal antibody that coats bacteria and maintains the microbiome homeostasis, while TD-IgA undergoes somatic hypermutation and reacts against specific antigens. The precursors of these TI- and TD-IgA have been controversial, but it has recently been demonstrated that TI IgA+ cells are derived from peritoneal B-1b cells while TD IgA+ cells are from germinal center B-2 cells. It is generally considered that these B-1b and B-2 cells are ultimately produced by hematopoietic stem cells (HSCs) that reside in the bone marrow (BM). However, our and others' prior work has shown that B-1b cells are also produced by HSC-independent fetal progenitors during embryonic development. Our lineage tracing data indicated that IgA+ cells in the lamina propria (LP) are derived from embryonic day (E) 7.5 endothelial cells (ECs), three days before the first HSC production in the embryo. Our lineage tracing system using EC-derived (Cdh5CreERT2) and HSC- derived (Fgd5CreERT2) enables us to segregate IgA+ cells in the LP of different origins. Thus, the central hypothesis of this project is that IgA+ cells in the LP consists of cells with different origins: fetal (EC)- and HSC- derived and that IgA+ cells of different origins have different roles against gut injury and infections. To test our hypothesis, in Aim1, we will examine TI- and TD- class switching of fetal- and HSC-derived B cells. We will also visualize these fetal- and HSC-derived TI- and TD- IgA+ cells using scRNA-sequencing and BCR repertoire- sequencing and will display the molecular differences of these cells. In Aim 2, we will examine the protective roles of fetal- and HSC-derived IgA+ cells against GI infection with C. rodentium. The results obtained from this proposal will establish a new paradigm of the developmental origin of IgA+ cells and their functions in the gut homeostasis and infections.