Early-life programming of mesenteric lymph node stromal cell identity by the lymphotoxin pathway regulates adult mucosal immunity

Abstract

Redundant mechanisms support immunoglobulin A (IgA) responses to intestinal antigens. These include multiple priming sites [mesenteric lymph nodes (MLNs), Peyer’s patches, and isolated lymphoid follicles] and various cytokines that promote class switch to IgA, even in the absence of T cells. Despite these backup 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 the lymphotoxin (LT) pathway—known to support IgA responses—at different developmental stages. We found that LT-β receptor (LTβR) signaling 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 LTβR signaling dictates the phenotype and function of MLN stromal cells to support IgA responses in the adult. Collectively, our studies uncover new mechanistic insights into how early-life LTβR signaling affects mucosal immune responses during adulthood.

Epigenomics and Early Life Human Humoral Immunity: Novel Paradigms and Research Opportunities

“…Similar findings have been reported by three additional birth cohorts that have used microbiome and/or host transcriptomic approaches to establish a longitudinal link between the early-life nasal microbiome and the subsequent risk of respiratory diseases ( 56 , 59 – 61 ). It is important to note that the latter human-based data are consistent with the substantial collection of accumulated evidence in animal models showing that specific microbial populations during early development can lead to immune-related abnormalities later in life ( 17 , 22 , 62 – 66 ). Taken together, all these longitudinal systems-level analyses from diverse birth cohorts provide strong support to the concept that environmental exposures taking place during the first weeks of life have a critical influence on the stereotypical development of the immune system in humans.…”

“…Several studies have contributed to elucidate the molecular program that controls early life antibody production ( 3 , 22 – 26 ). This immune developmental program includes cardinal molecules that orchestrate cell-to-cell interactions and transcription factors that integrate these signals and modify cellular phenotypes according to stereotypical maturational stages ( 16 , 27 ).…”

“…Pro-apoptotic signals delivered by ligands such as Fas ligand/TNFSF6 or TRAIL/TNFSF10 are critical for lymphocyte selection and development of lymphoid tissues ( 24 , 36 ). Others, like lymphotoxin β/TNFSF3, a membrane-bound LTα and β complex, regulate GC formation and during early life, may imprint mucosal IgA responses and ASC generation ( 22 ). The generation of ASC also involves specific intracellular changes encoded in a transcriptional program driven by master transcription factors of ASC differentiation ( 18 , 19 , 37 ).…”

“…Despite the fact that early life antibody production has distinct features in humans ( 12 , 15 , 23 ), and that early exposures and consequent shaping of B-cells and ASC identity and function are unique to human infants ( 22 , 52 ), most research in this field has focused on animal models or human adults and many aspects of how antibody generation is established and occurs during the first a few years of life are not fully understood. However, in recent years several new technological approaches have shown great potential to move forward the emerging field of human systems immunology ( 53 , 54 ).…”

Crosstalk Between Platelets and Microbial Pathogens

“…TGF-β is a key factor in IgA isotype switching ( 68 ). Since IgA plays an important role in controlling the homeostasis of gut microbiota ( 68 ), and preventing pathogen invasion at mucosal sites ( 69 ), it remains to be investigated whether platelet TGF-β contributes to the production of intestinal IgA. In addition, TGF-β is critical for the differentiation of regulatory T cells under non-inflammatory conditions, in both mice and humans ( 70 – 72 ).…”