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Molecular definition of group 1 innate lymphoid cells in the mouse uterus.

ABSTRACT: Determining the function of uterine lymphocytes is challenging because of the dynamic changes in response to sex hormones and, during pregnancy, to the invading foetal trophoblast cells. Here we provide a genome-wide transcriptome atlas of mouse uterine group 1 innate lymphoid cells (ILCs) at mid-gestation. Tissue-resident Eomes⁺CD49a⁺ NK cells (trNK), which resemble human uterine NK cells, are most abundant during early pregnancy, and have gene signatures associated with TGF-? responses and interactions with trophoblast, epithelial, endothelial, smooth muscle cells, leucocytes and extracellular matrix. Conventional NK cells expand late in gestation and may engage in crosstalk with trNK cells involving IL-18 and IFN-?. Eomes^-CD49a⁺ ILC1s dominate before puberty, and specifically expand in second pregnancies when the expression of the memory cell marker CXCR6 is upregulated. These results identify trNK cells as the cellular hub of uterine group 1 ILCs, and mark CXCR6⁺ ILC1s as potential memory cells of pregnancy.

SUBMITTER: Filipovic I

PROVIDER: S-EPMC6206068 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Molecular definition of group 1 innate lymphoid cells in the mouse uterus.

Filipovic Iva I Chiossone Laura L Vacca Paola P Hamilton Russell S RS Ingegnere Tiziano T Doisne Jean-Marc JM Hawkes Delia A DA Mingari Maria Cristina MC Sharkey Andrew M AM Moretta Lorenzo L Colucci Francesco F

Nature communications 20181029 1

Determining the function of uterine lymphocytes is challenging because of the dynamic changes in response to sex hormones and, during pregnancy, to the invading foetal trophoblast cells. Here we provide a genome-wide transcriptome atlas of mouse uterine group 1 innate lymphoid cells (ILCs) at mid-gestation. Tissue-resident Eomes<sup>+</sup>CD49a<sup>+</sup> NK cells (trNK), which resemble human uterine NK cells, are most abundant during early pregnancy, and have gene signatures associated with T ...[more]

PMID: 30374017

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Project description:Background & aimsSevere injury to the lining of the stomach leads to changes in the epithelium (reprogramming) that protect and promote repair of the tissue, including development of spasmolytic polypeptide-expressing metaplasia (SPEM) and tuft and foveolar cell hyperplasia. Acute gastric damage elicits a type-2 inflammatory response that includes production of type-2 cytokines and infiltration by eosinophils and alternatively activated macrophages. Stomachs of mice that lack interleukin 33 (IL33) or interleukin 13 (IL13) did not undergo epithelial reprogramming after drug-induced injury. We investigated the role of group 2 innate lymphoid cells (ILC2s) in gastric epithelial repair.MethodsAcute gastric injury was induced in C57BL/6J mice (wild-type and RAG1 knockout) by administration of L635. We isolated ILC2s by flow cytometry from stomachs of mice that were and were not given L635 and performed single-cell RNA sequencing. ILC2s were depleted from wild-type and RAG1-knockout mice by administration of anti-CD90.2. We assessed gastric cell lineages, markers of metaplasia, inflammation, and proliferation. Gastric tissue microarrays from patients with gastric adenocarcinoma were analyzed by immunostaining.ResultsThere was a significant increase in the number of GATA3-positive ILC2s in stomach tissues from wild-type mice after L635-induced damage, but not in stomach tissues from IL33-knockout mice. We characterized a marker signature of gastric mucosal ILC2s and identified a transcription profile of metaplasia-associated ILC2s, which included changes in expression of Il5, Il13, Csf2, Pd1, and Ramp3; these changes were validated by quantitative polymerase chain reaction and immunocytochemistry. Depletion of ILC2s from mice blocked development of metaplasia after L635-induced injury in wild-type and RAG1-knockout mice and prevented foveolar and tuft cell hyperplasia and infiltration or activation of macrophages after injury. Numbers of ILC2s were increased in stomach tissues from patients with SPEM compared with patients with normal corpus mucosa.ConclusionsIn analyses of stomach tissues from mice with gastric tissue damage and patients with SPEM, we found evidence of type 2 inflammation and increased numbers of ILC2s. Our results suggest that ILC2s coordinate the metaplastic response to severe gastric injury.

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Molecular definition of group 1 innate lymphoid cells in the mouse uterus.

Publications

Molecular definition of group 1 innate lymphoid cells in the mouse uterus.

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