GSE138456
Early Life Programming of Mesenteric Lymph Node Stromal Cell Identity by the Lymphotoxin Pathway Regulates Mucosal Immune Responses in the Adult (Stromal cells)
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 (LTßR) signalling in early life 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, early life LTßR 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 early life LTßR signalling impacts mucosal immune responses during adulthood. Overall design: RNA profiles of MLN stromal cells sorted from of day8-rotavirus infected WT mice that were treated at E14/E17 with LTbR-Ig (labeled as “PPless” in the sample names) or control Ig (labeled as “WT”), were generated by deep sequencing, in quadruplicate, using Illumina NextSeq500