Small Intestinal Goblet Cells Control Humoral Immune Responses and Mobilization During Enteric Infection.

Abstract

Humoral immune responses within the gut play diverse roles including pathogen clearance during enteric infections, maintaining tolerance, and facilitating the assemblage and stability of the gut microbiota. How these humoral immune responses are initiated and contribute to these processes are well studied. However, the signals promoting the expansion of these responses and their rapid mobilization to the gut mucosa are less well understood. Intestinal goblet cells form goblet cell-associated antigen passages (GAPs) to deliver luminal antigens to the underlying immune system and facilitate tolerance. GAPs are rapidly inhibited during enteric infection to prevent inflammatory responses to innocuous luminal antigens. Here we interrogate GAP inhibition as a key physiological response required for effective humoral immunity. Independent of infection, GAP inhibition resulted in enrichment of transcripts representing B cell recruitment, expansion, and differentiation into plasma cells in the small intestine (SI), which were confirmed by flow cytometry and ELISpot assays. Further we observed an expansion of isolated lymphoid follicles within the SI, as well as expansion of plasma cells in the bone marrow upon GAP inhibition. S1PR1-induced blockade of leukocyte trafficking during GAP inhibition resulted in a blunting of SI plasma cell expansion, suggesting that mobilization of plasma cells from the bone marrow contributes to their expansion in the gut. However, luminal IgA secretion was only observed in the presence of S. typhimurium infection, suggesting that although GAP inhibition mobilizes a mucosal humoral immune response, a second signal is required for full effector function. Overriding GAP inhibition during enteric infection abrogated the expansion of laminar propria IgA+ plasma cells. We conclude that GAP inhibition is a required physiological response for efficiently mobilizing mucosal humoral immunity in response to enteric infection.