Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal; Lydia Becker Institute for Immunology & Infection, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
Maurice Müller Laboratories, Department for Biomedical Research, University of Bern, Bern, Switzerland; Department of Visceral Surgery and Medicine, Bern University Hospital, University of Bern, Bern, Switzerland.
Cell Rep. 2023 Feb 28;42(2):112074. doi: 10.1016/j.celrep.2023.112074. Epub 2023 Feb 13.
Immune development is profoundly influenced by vertically transferred cues. However, little is known about how maternal innate-like lymphocytes regulate offspring immunity. Here, we show that mice born from γδ T cell-deficient (TCRδ) dams display an increase in first-breath-induced inflammation, with a pulmonary milieu selectively enriched in type 2 cytokines and type 2-polarized immune cells, when compared with the progeny of γδ T cell-sufficient dams. Upon helminth infection, mice born from TCRδ dams sustain an increased type 2 inflammatory response. This is independent of the genotype of the pups. Instead, the offspring of TCRδ dams harbors a distinct intestinal microbiota, acquired during birth and fostering, and decreased levels of intestinal short-chain fatty acids (SCFAs), such as pentanoate and hexanoate. Importantly, exogenous SCFA supplementation inhibits type 2 innate lymphoid cell function and suppresses first-breath- and infection-induced inflammation. Taken together, our findings unravel a maternal γδ T cell-microbiota-SCFA axis regulating neonatal lung immunity.
免疫发育受到垂直传递线索的深刻影响。然而，对于母体先天样淋巴细胞如何调节后代免疫，人们知之甚少。在这里，我们发现与 γδ T 细胞充足（TCRδ）母鼠所生的后代相比，来自 γδ T 细胞缺陷（TCRδ）母鼠的小鼠在第一次呼吸时会引发炎症增加，肺部环境中选择性富含 2 型细胞因子和 2 型极化的免疫细胞。与 TCRδ 母鼠所生的幼崽相比，在感染寄生虫时，来自 TCRδ 母鼠的幼崽会持续产生更强的 2 型炎症反应。这与幼崽的基因型无关。相反，TCRδ 母鼠的后代具有独特的肠道微生物群，这些微生物群在出生和养育期间获得，并降低了肠道短链脂肪酸（SCFA）的水平，如戊酸和己酸。重要的是，外源性 SCFA 补充抑制了 2 型先天淋巴细胞的功能，并抑制了第一次呼吸和感染引起的炎症。总之，我们的研究结果揭示了一条调节新生儿肺部免疫的母体 γδ T 细胞-微生物群-SCFA 轴。
