Perinatal Programming of Mucosal Stromal Cell Identity by the Lymphotoxin Pathway Regulates Mucosal Immune Responses in the Adult

Abstract

Redundant mechanisms support IgA responses to intestinal antigens. These include multiple priming sites (mesenteric lymph nodes (MLN), Peyer’s patches and isolated lymphoid follicles) and various cytokines that promote class switch to IgA, even in the absence of T cells. In spite of these back-up mechanisms, vaccination against enteric pathogens such as Rotavirus has limited success in some populations. Genetic and environmental signals experienced during early life are known to influence mucosal immunity, yet the mechanisms for how these exposures operate remain unclear. Here we used Rotavirus infection to follow antigen-specific IgA responses through time and in different gut compartments. Using genetic and pharmacological approaches, we tested the role of a pathway known to support IgA responses (Lymphotoxin – LT) at different developmental stages. We found that LT-beta receptor (LTβR) signalling in utero programs intestinal IgA responses in adulthood by affecting antibody class switch recombination to IgA and subsequent generation of IgA antibody-secreting cells within an intact MLN. In addition, in utero LTβR signalling dictates the phenotype and function of MLN stromal cells in order to support IgA responses in the adult. Collectively, our studies uncover new mechanistic insights into how in utero LTβR signalling impacts mucosal immune responses during adulthood. One Sentence Summary Early life LTβR signalling is critical for programming the mesenteric lymph node stromal cell environment, impacting both antibody isotype switching to IgA and the differentiation of IgA+ antibody secreting cells. Graphic Abstract