γδ Intraepithelial Lymphocytes Facilitate Pathological Epithelial Cell Shedding Via CD103-Mediated Granzyme Release.
γδ Intraepithelial Lymphocytes Facilitate Pathological Epithelial Cell Shedding Via CD103-Mediated Granzyme Release.
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DOI：
10.1053/j.gastro.2021.11.028
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发表时间：
2022-03
期刊：
影响因子：
29.4
通讯作者：
Edelblum KL
中科院分区：
文献类型：
--
作者：
Hu MD;Golovchenko NB;Burns GL;Nair PM;Kelly TJ 4th;Agos J;Irani MZ;Soh WS;Zeglinski MR;Lemenze A;Bonder EM;Sandrock I;Prinz I;Granville DJ;Keely S;Watson AJM;Edelblum KL
在炎症性肠病中观察到凋亡肠细胞过度脱落到肠腔中，并且与疾病复发相关。基于它们的细胞溶解能力和监视行为，我们研究了表达γδ T细胞受体（γδ IEL）的上皮内淋巴细胞是否积极参与肠上皮细胞脱落到管腔中。对用腹膜内（i. p.）脂多糖（LPS，10 mg/kg）处理90分钟以诱导肿瘤坏死因子（TNF）介导的凋亡。在存在或不存在封闭抗体的情况下，通过对ZO-1漏斗和裂解的胱天蛋白酶-3（CC 3）进行免疫染色来定量各种敲除或转基因小鼠中的细胞脱落。通过ELISA定量来自离体刺激的γδ IEL的GzmA和GzmB释放。对来自对照和克罗恩病患者的十二指肠和回肠活检进行γδ T细胞受体（TCR）和CC 3的免疫染色。LPS处理的小鼠的活体显微镜检查显示γδ IEL与脱落的肠细胞进行了延长的接触。这些延长的相互作用需要CD 103与E-钙粘蛋白的结合，并且CD 103敲除或阻断显著减少了LPS诱导的脱落。此外，我们发现，颗粒酶A和B，而不是穿孔素，细胞脱落所需的。这些细胞外颗粒酶由γδ IEL组成性地和在CD 103/E-钙粘蛋白连接后释放。此外，我们发现与健康对照相比，克罗恩病活检组织中γδ IEL定位于CC 3阳性肠细胞的频率增加。我们的研究结果揭示了γδ IEL在通过CD 103介导的细胞外颗粒酶释放促进TNF介导的凋亡肠细胞脱落中的先前未被认识的作用。前哨组织驻留T细胞促进上皮细胞的挤出，上皮细胞经历程序性细胞死亡，以响应通过整合素介导的细胞外丝氨酸蛋白酶释放的促炎信号。
Excessive shedding of apoptotic enterocytes into the intestinal lumen is observed in inflammatory bowel disease and is correlated with disease relapse. Based on their cytolytic capacity and surveillance behavior, we investigated whether intraepithelial lymphocytes expressing the γδ T cell receptor (γδ IELs) are actively involved in the shedding of enterocytes into the lumen. Intravital microscopy was performed on GFP γδ T cell reporter mice treated with intraperitoneal (i.p.) lipopolysaccharide (LPS, 10 mg/kg) for 90 min to induce tumor necrosis factor (TNF)-mediated apoptosis. Cell shedding in various knockout or transgenic mice in the presence or absence of blocking antibody was quantified by immunostaining for ZO-1 funnels and cleaved caspase-3 (CC3). GzmA and GzmB release from ex vivo stimulated γδ IELs was quantified by ELISA. Immunostaining for γδ T cell receptor (TCR) and CC3 was performed on duodenal and ileal biopsies from control and Crohn’s disease patients. Intravital microscopy of LPS-treated mice revealed that γδ IELs make extended contact with shedding enterocytes. These prolonged interactions require CD103 engagement by E-cadherin, and CD103 knockout or blockade significantly reduced LPS-induced shedding. Furthermore, we find that granzymes A and B, but not perforin, are required for cell shedding. These extracellular granzymes are released by γδ IELs both constitutively and following CD103/E-cadherin ligation. Moreover, we find that the frequency of γδ IEL localization to CC3-positive enterocytes is increased in Crohn’s disease biopsies compared to healthy controls. Our results uncover a previously unrecognized role for γδ IELs in facilitating TNF-mediated shedding of apoptotic enterocytes via CD103-mediated extracellular granzyme release. Sentinel tissue-resident T cells facilitate the extrusion of epithelial cells undergoing programmed cell death in response to pro-inflammatory signals via integrin-mediated extracellular serine protease release.
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影响因子：
5.4
作者：
ISAAZ, S;BAETZ, K;GRIFFITHS, GM
通讯作者：
GRIFFITHS, GM
影响因子：
29.4
作者：
Edelblum KL;Singh G;Odenwald MA;Lingaraju A;El Bissati K;McLeod R;Sperling AI;Turner JR
通讯作者：
Turner JR
影响因子：
35.7
作者：
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通讯作者：
Naghavi, Mohsen
影响因子：
16.6
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Hiroyasu S;Zeglinski MR;Zhao H;Pawluk MA;Turner CT;Kasprick A;Tateishi C;Nishie W;Burleigh A;Lennox PA;Van Laeken N;Carr NJ;Petersen F;Crawford RI;Shimizu H;Tsuruta D;Ludwig RJ;Granville DJ
通讯作者：
Granville DJ
影响因子：
29.4
作者：
Marchiando AM;Shen L;Graham WV;Edelblum KL;Duckworth CA;Guan Y;Montrose MH;Turner JR;Watson AJ
通讯作者：
Watson AJ