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γδ intraepithelial lymphocytes facilitate pathological epithelial cell shedding via CD103-mediated granzyme release.
bioRxiv - Immunology Pub Date : 2021-01-22 , DOI: 10.1101/2021.01.20.427150
Madeleine D. Hu , Natasha B. Golovchenko , Thomas J. Kelly , Jonathan Agos , Matthew R. Zeglinski , Edward M. Bonder , David J. Granville , Alastair J.M. Watson , Karen L Edelblum

Excessive shedding of enterocytes into the intestinal lumen is observed in inflammatory bowel disease and is correlated with disease relapse. However, the mechanisms underlying this phenomenon remain unclear. Intraepithelial lymphocytes (IEL) expressing the γδ T-cell receptor (TCR) provide surveillance of the intestinal mucosa at steady-state, which is regulated, in part, by CD103. Intravital microscopy of lipopolysaccharide (LPS)-treated mice revealed that γδ IELs make extended contact with shedding enterocytes. These prolonged interactions require CD103 engagement by E-cadherin, as CD103 blockade significantly reduces LPS-induced shedding. Furthermore, we find that granzymes A and B, but not perforin, are required for cell shedding, and that these granzymes are released by γδ IELs both constitutively and following CD103/E-cadherin ligation. These findings indicate that extracellular granzyme facilitates shedding, likely through cleavage of extracellular matrix proteins. Our results uncover a previously unrecognized role for γδ IELs in facilitating pathological cell shedding in a CD103- and granzyme-dependent manner.

中文翻译:

γδ上皮内淋巴细胞通过CD103介导的颗粒酶释放促进病理上皮细胞脱落。

在炎症性肠病中观察到肠细胞过度进入肠腔,并且与疾病复发相关。但是,这种现象的潜在机制仍不清楚。表达γδT细胞受体(TCR)的上皮内淋巴细胞(IEL)提供了对肠粘膜处于稳态的监视,该监视部分受CD103调节。脂多糖(LPS)处理的小鼠的活体内显微镜检查显示,γδIEL与脱落的肠上皮细胞进行了长期接触。这些长时间的相互作用需要E-cadherin参与CD103的参与,因为CD103的阻滞作用会大大减少LPS诱导的脱落。此外,我们发现细胞脱落需要颗粒酶A和B,而不需要穿孔素,并且这些颗粒酶由γδIEL组成性地和CD103 / E-钙粘蛋白连接后释放。这些发现表明,细胞外颗粒酶可能通过切割细胞外基质蛋白来促进脱落。我们的结果揭示了γδIELs以前无法识别的作用,以CD103和颗粒酶依赖性方式促进病理性细胞脱落。
更新日期:2021-01-24
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