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Matrix metalloproteinases cleave membrane-bound PD-L1 on CD90+ (myo-)fibroblasts in Crohn's disease and regulate Th1/Th17 cell responses.
International Immunology ( IF 4.8 ) Pub Date : 2020-01-09 , DOI: 10.1093/intimm/dxz060
Jose E Aguirre 1, 2 , Ellen J Beswick 3 , Carl Grim 1 , Gabriela Uribe 1, 4 , Marissa Tafoya 5 , Gabriela Chacon Palma 6 , Von Samedi 6 , Rohini McKee 7 , Romain Villeger 1 , Yuriy Fofanov 8 , Yingzi Cong 9 , Gregory Yochum 10 , Walter Koltun 11 , Don Powell 1, 2 , Irina V Pinchuk 1, 2, 4, 9
Affiliation  

Increased T helper (Th)1/Th17 immune responses are a hallmark of Crohn's disease (CD) immunopathogenesis. CD90+ (myo-)fibroblasts (MFs) are abundant cells in the normal (N) intestinal mucosa contributing to mucosal tolerance via suppression of Th1 cell activity through cell surface membrane-bound PD-L1 (mPD-L1). CD-MFs have a decreased level of mPD-L1. Consequently, mPD-L1-mediated suppression of Th1 cells by CD-MFs is decreased, yet the mechanism responsible for the reduction in mPDL-1 is unknown. Increased expression of matrix metalloproteinases (MMPs) has been reported in CD. Herein we observed that when compared to N- and ulcerative colitis (UC)-MFs, CD-MFs increase in LPS-inducible levels of MMP-7 and -9 with a significant increase in both basal and inducible MMP-10. A similar pattern of MMP expression was observed in the CD-inflamed mucosa. Treatment of N-MFs with a combination of recombinant human MMP-7, -9 and -10 significantly decreased mPD-L1. In contrast, inhibition of MMP activity with MMP inhibitors or anti-MMP-10 neutralizing antibodies restores mPD-L1 on CD-MFs. CD-MFs demonstrated reduced capacity to suppress Th1 and Th17 responses from activated CD4+ T cells. By contrast, supplementation of the CD-MF:T-cell co-cultures with MMP inhibitors or anti-MMP neutralizing antibodies restored the CD-MF-mediated suppression. Our data suggest that (i) increased MMP-10 expression by CD-MFs and concomitant cleavage of PD-L1 from the surface of CD-MFs are likely to be one of the factors contributing to the decrease of mPD-L1-mediated suppression of Th1/Th17 cells in CD; and (ii) MMPs are likely to have a significant role in the intestinal mucosal immune responses.

中文翻译:

基质金属蛋白酶在克罗恩病中切割CD90 +(肌)成纤维细胞上的膜结合PD-L1,并调节Th1 / Th17细胞反应。

T辅助(Th)1 / Th17免疫反应增强是克罗恩病(CD)免疫发病机制的标志。CD90 +(肌)成纤维细胞(MFs)是正常(N)肠粘膜中的丰富细胞,通过抑制细胞表面膜结合的PD-L1(mPD-L1)的Th1细胞活性,有助于粘膜耐受。CD-MF的mPD-L1水平降低。因此,减少了CD-MF介导的mPD-L1介导的Th1细胞抑制作用,但导致mPDL-1减少的机制尚不清楚。已有报道CD中基质金属蛋白酶(MMP)的表达增加。在本文中,我们观察到,与N和溃疡性结肠炎(UC)-MFs相比,CD-MFs在LPS诱导的MMP-7和-9水平上增加,而基础MMP-10和诱导型MMP-10均显着增加。在CD感染的粘膜中观察到了类似的MMP表达模式。用重组人MMP-7,-9和-10组合治疗N-MF,可显着降低mPD-L1。相反,用MMP抑制剂或抗MMP-10中和抗体抑制MMP活性可恢复CD-MF上的mPD-L1。CD-MFs抑制CD4 + T细胞激活Th1和Th17反应的能力降低。相反,用MMP抑制剂或抗MMP中和抗体补充CD-MF:T细胞共培养物可恢复CD-MF介导的抑制作用。我们的数据表明(i)CD-MFs增强MMP-10表达,并伴随CD-MFs切割PD-L1可能是导致mPD-L1介导的MPD-10抑制作用降低的因素之一。 CD中的Th1 / Th17细胞;
更新日期:2019-11-01
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