Multikingdom generation and tissue maintenance of splenic IGA plasma cells

The National Institute of Allergy and Infectious Diseases awarded the University of Massachusetts Medical School $251,250 on September 3, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to support research into the generation and tissue maintenance of splenic IgA plasma cells.

The research investigates how B lymphocytes responding to commensal microbes in the gut generate IgA-secreting plasma cells that localize to the spleen and other systemic sites. IgA is essential for preventing commensal outgrowth and maintaining intestinal homeostasis, yet the mechanisms regulating extra-gut IgA responses remain poorly understood. The project tests the hypothesis that commensal bacteria and fungi generate qualitatively different IgA responses that endow plasma cells with distinct migratory receptors, directing them to specific sub-anatomical niches within the spleen. The research also examines whether intracellular signaling differs in IgA plasma cells found in different splenic regions, determining their residency or egress. The work identifies intrinsic and extrinsic cues that drive IgA plasma cell generation and positioning.

The award is classified as a Project Grant, a standard assistance type under NIAID's research funding portfolio. Work is performed in Worcester, Massachusetts, with a period of performance from September 3, 2026, through August 31, 2028.

Abstract

B lymphocytes that come in contact with commensal microbes in the GUT mount a specific response that leads to the generation of immunoglobulin a (IGA)-secreting plasma cells. IGA is essential for preventing commensal outgrowth and maintaining intestinal homeostasis. Indeed, IGA-secreting plasma cells are routinely localized in the intestinal lamina propria, where they can secrete antibody in the GUT lumen. However, IGA can be easily measured in circulation in human and mice, and IGA-secreting plasma cells can be found in the bone marrow, pointing to a systemic IGA response. Our preliminary data support the existence of a novel, complex niche for IGA-secreting plasma cells in the spleen, which might underpin both systemic and local humoral immunity. However, the regulation of extra-GUT IGA response remains poorly understood. Therefore, elucidating the fundamental mechanisms that regulate the generation and maintenance of IGA- secreting plasma cells in the spleen represents a central, unanswered, question in tissue immunology. Previous research has identified IGA response against different commensal kingdoms, and suggests that IGA- secreting plasma cells might be transcriptional and functional different to IGG- and IGM-secreting plasma cells. However, the extrinsic and intrinsic signals that control the generation and positioning of IGA plasma cells in the spleen remain unknown. In this application we test the hypothesis that commensal bacteria and commensal fungi generate a qualitatively different IGA response. This response endows IGA plasma cells with migratory receptors that direct them to distinct sub-anatomical niches in the spleen. We also hypothesize that intracellular signaling differs in IGA plasma cells found in different area of the spleen, dictating their residency or egress. Our aims are: 1) to identify the intrinsic and extrinsic cues that drive IGA plasma cells in anatomical niches, with special focus on migratory receptors that control IGA PC position in the spleen and their role in supporting a protective humoral response against pathogens from different kingdoms; and 2) to dissect signaling pathways that regulate IGA plasma cells residency in the spleen. The proposed studies examine the poorly understood generation and maintenance of IGA plasma cells found in the spleen. IT is our expectation that these studies will increase our understanding of how intestinal commensals shapes b cell responses at distal anatomical sites from the GUT. Furthermore, these studies will provide a foundation for a better understanding of the relationship between different commensal kingdoms and humoral immunity in tissues and circulation.