Early-life programming of mesenteric lymph node stromal cell identity by the lymphotoxin pathway regulates adult mucosal immunity
Early-life programming of mesenteric lymph node stromal cell identity by the lymphotoxin pathway regulates adult mucosal immunity
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DOI：
10.1126/sciimmunol.aax1027
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发表时间：
2019-12-01
影响因子：
24.8
通讯作者：
Gommerman, Jennifer L.
中科院分区：
文献类型：
--
作者：
Li, Conglei;Lam, Evelyn;Gommerman, Jennifer L.
多余的机制支持免疫球蛋白A(IgA)对肠道抗原的反应。其中包括多个启动部位[肠系膜淋巴结(MLN)、Peyer‘s补片和孤立的淋巴滤泡]和各种细胞因子，即使在没有T细胞的情况下，这些细胞因子也能促进类免疫球蛋白A的转换。尽管有这些后备机制，但针对轮状病毒等肠道病原体的疫苗接种在一些人群中成效有限。众所周知，早期生命中经历的遗传和环境信号会影响粘膜免疫，但这些暴露如何运作的机制尚不清楚。在这里，我们使用轮状病毒感染来跟踪不同肠段的抗原特异性IgA反应。利用遗传学和药理学方法，我们测试了淋巴毒素(LT)途径在不同发育阶段的作用，淋巴毒素(LT)是已知的支持IgA反应的途径。我们发现，生命早期的LT-β受体(LT-beta R)信号通过影响抗体类切换到IgA的重组以及随后在完整的MLN中产生IgA抗体分泌细胞来计划成年后肠道的IgA反应。此外，早期LTβR信号决定了MLN基质细胞的表型和功能，以支持成人的IgA反应。总而言之，我们的研究揭示了关于早期生命LTβR信号如何影响成年期粘膜免疫反应的新的机械性见解。
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-beta receptor (LT beta R) 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 LT beta R 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 LT beta R signaling affects mucosal immune responses during adulthood.