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

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Science Immunology  20 Dec 2019:
Vol. 4, Issue 42, eaax1027
DOI: 10.1126/sciimmunol.aax1027

Early-Life Licensing of Antiviral IgA Immunity

Mucosal immune responses after exposure to pathogens are influenced by multiple factors, including key developmental milestones achieved before birth or during the neonatal period. Li et al. investigated when during mouse immune system development signals initiated by lymphotoxin (LT) expression are needed to enable an effective mucosal IgA antibody response after rotavirus infection of adult mice. Transient interruption of signaling by the LT receptor during late embryonic life was sufficient to induce persistent defects in stromal cells resident in the mesenteric lymph node that impaired the IgA antirotavirus response of adult mice without interfering with IgA responses to commensal bacteria. These findings highlight the pivotal role early-life exposures play in configuring the mammalian immune system.


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.

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