TLR4 activation enhances the PD-L1-mediated tolerogenic capacity of colonic CD90+ stromal cells.
TLR4 activation enhances the PD-L1-mediated tolerogenic capacity of colonic CD90+ stromal cells.
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DOI：
10.4049/jimmunol.1203441
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发表时间：
2014-09-01
期刊：
影响因子：
--
通讯作者：
Pinchuk IV
中科院分区：
文献类型：
--
作者：
Beswick EJ;Johnson JR;Saada JI;Humen M;House J;Dann S;Qiu S;Brasier AR;Powell DW;Reyes VE;Pinchuk IV
通过程序性死亡配体（PD-L）-1和PD-L2的信号传导对于维持外周耐受性至关重要。CD 90+肌成纤维细胞/成纤维细胞（CMF）是正常人结肠粘膜中主要的PD-1配体表达细胞。CMF通过PD-1配体抑制活化的CD 4 + T细胞增殖。尚不清楚通过TLR的信号传导是否有助于在结肠粘膜耐受后调节CMF上的PD-1配体。在此，我们证明了人CMFs上的TLR 4的刺激上调PD-L1，但不上调PD-L2，并加强CMFs介导的对CD 4 + T细胞增殖和IFN-γ产生的抑制。TLR 4介导的CMF上PD-L 1上调涉及NF-κB途径，并且具有JAK 2和MyD 88依赖性。TLR 1/2和TLR 5的MyD 88依赖性刺激也上调了培养物中CMFs上的PD-L1表达。PD-L1表达在体内在缺乏MyD 88的小鼠的结肠粘膜中显著降低。在成纤维细胞特异性MyD 88条件性敲除小鼠中诱导CMF中的MyD 88缺陷导致粘膜IFN-γ表达强烈增加，同时在稳态和葡聚糖硫酸钠诱导的上皮损伤下消除CMF中的PD-L1表达。这些数据共同表明，正常结肠粘膜中CMF的MyD 88依赖性TLR刺激可以增强这些细胞的抗炎能力，从而有助于维持粘膜耐受性。
Signaling via Programmed Death Ligand (PD-L)-1 and PD-L2 is crucial for maintaining peripheral tolerance. CD90+ myofibroblasts/fibroblasts (CMFs) are major PD-1 ligands -expressing cells in normal human colonic mucosa. CMFs suppress activated CD4+ T cell proliferation via PD-1 ligands. It is not known whether signaling through TLRs contribute to the regulation PD-1 ligands on CMFs upon colonic mucosal tolerance. Herein, we demonstrated that stimulation of TLR4 on human CMFs upregulates PD-L1, but not PD-L2, and reinforces CMF-mediated suppression of CD4+ T cell proliferation and IFN-γ production. TLR4-mediated upregulation of PD-L1 on CMFs involved NF-κB pathways and was JAK2- and MyD88-dependent. MyD88-dependent stimulation of TLR1/2 and TLR 5 also upregulated PD-L1 expression on CMFs in culture. PD-L1 expression was drastically decreased in vivo in the colonic mucosa of mice devoid of MyD88. Induction of MyD88 deficiency in CMFs in fibroblast-specific MyD88 conditional knockout mice resulted in a strong increase in a mucosal IFN-γ expression concomitantly with the abrogation of PD-L1 expression in CMFs under homeostasis and epithelial injury induced by dextran sodium sulfate. Together these data suggest that MyD88-dependent TLR stimulation of CMFs in the normal colonic mucosa may reinforce these cells' anti-inflammatory capacity, and thus contribute to the maintenance of mucosal tolerance.
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T细胞共刺激和共抑制的分子机制。
DOI：
10.1038/nri3405
发表时间：
2013-04
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
17.1
作者：
Amarnath S;Mangus CW;Wang JC;Wei F;He A;Kapoor V;Foley JE;Massey PR;Felizardo TC;Riley JL;Levine BL;June CH;Medin JA;Fowler DH
通讯作者：
Fowler DH
影响因子：
5.6
作者：
Abe, Miyuki;Funakoshi-Tago, Megumi;Kasahara, Tadashi
通讯作者：
Kasahara, Tadashi
影响因子：
20.3
作者：
Green, Michael R.;Monti, Stefano;Shipp, Margaret A.
通讯作者：
Shipp, Margaret A.
影响因子：
3.7
作者：
Li G;Liu D;Zhang Y;Qian Y;Zhang H;Guo S;Sunagawa M;Hisamitsu T;Liu Y
通讯作者：
Liu Y