Interferon-gamma drives programmed death-ligand 1 expression on islet β cells to limit T cell function during autoimmune diabetes.
Interferon-gamma drives programmed death-ligand 1 expression on islet β cells to limit T cell function during autoimmune diabetes.
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DOI：
10.1038/s41598-018-26471-9
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发表时间：
2018-05-29
影响因子：
4.6
通讯作者：
Fife BT
中科院分区：
文献类型：
--
作者：
Osum KC;Burrack AL;Martinov T;Sahli NL;Mitchell JS;Tucker CG;Pauken KE;Papas K;Appakalai B;Spanier JA;Fife BT
1型糖尿病由自身反应性T细胞介导的β细胞破坏引起。尽管共抑制受体程序性死亡-1（PD-1）抑制自身免疫，但其同源配体在β细胞上的表达和调控尚不清楚。在这里，我们询问了小鼠和人类胰岛中β细胞内在程序性死亡配体-1（PD-L1）的表达。我们测量了PD-L1表面表达水平和PD-L1+ β细胞频率的显著增加，因为非肥胖糖尿病（NOD）小鼠衰老并发展为糖尿病。β细胞PD-L1表达增加依赖于T细胞浸润，因为Rag 1缺陷小鼠的β细胞缺乏PD-L1。使用Rag 1缺陷型NOD小鼠胰岛，我们确定IFN-γ促进β细胞PD-L1表达。我们使用人体样本进行了类似的实验，发现与2型糖尿病、自身抗体阳性和非糖尿病样本相比，1型糖尿病样本中β细胞PD-L1表达显著增加。在1型糖尿病样本中，β细胞PD-L1表达与胰岛炎相关。来自非糖尿病个体的人胰岛的体外实验表明，IFN-γ促进β细胞PD-L1表达。这些结果表明，产生胰岛素的β细胞通过上调PD-L1表达以限制自身反应性T细胞来响应胰腺炎症和IFN-γ产生。
Type 1 diabetes is caused by autoreactive T cell-mediated β cell destruction. Even though co-inhibitory receptor programmed death-1 (PD-1) restrains autoimmunity, the expression and regulation of its cognate ligands on β cell remains unknown. Here, we interrogated β cell-intrinsic programmed death ligand-1 (PD-L1) expression in mouse and human islets. We measured a significant increase in the level of PD-L1 surface expression and the frequency of PD-L1+ β cells as non-obese diabetic (NOD) mice aged and developed diabetes. Increased β cell PD-L1 expression was dependent on T cell infiltration, as β cells from Rag1-deficient mice lacked PD-L1. Using Rag1-deficient NOD mouse islets, we determined that IFN-γ promotes β cell PD-L1 expression. We performed analogous experiments using human samples, and found a significant increase in β cell PD-L1 expression in type 1 diabetic samples compared to type 2 diabetic, autoantibody positive, and non-diabetic samples. Among type 1 diabetic samples, β cell PD-L1 expression correlated with insulitis. In vitro experiments with human islets from non-diabetic individuals showed that IFN-γ promoted β cell PD-L1 expression. These results suggest that insulin-producing β cells respond to pancreatic inflammation and IFN-γ production by upregulating PD-L1 expression to limit self-reactive T cells.
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DOI：
10.1084/jem.20061577
发表时间：
2006-11-27
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Fife BT;Guleria I;Gubbels Bupp M;Eagar TN;Tang Q;Bour-Jordan H;Yagita H;Azuma M;Sayegh MH;Bluestone JA
通讯作者：
Bluestone JA
影响因子：
4.4
作者：
Cantor, Joseph;Haskins, Kathryn
通讯作者：
Haskins, Kathryn
影响因子：
7.7
作者：
Bishop, Nicholas H.;Nelsen, Michelle K.;Gill, Ronald G.
通讯作者：
Gill, Ronald G.
影响因子：
15.9
作者：
Filippi, Christophe M.;Estes, Elizabeth A.;von Herrath, Matthias G.
通讯作者：
von Herrath, Matthias G.
影响因子：
7.7
作者：
Baas M;Besançon A;Goncalves T;Valette F;Yagita H;Sawitzki B;Volk HD;Waeckel-Enée E;Rocha B;Chatenoud L;You S
通讯作者：
You S