Matrix metalloproteinases cleave membrane-bound PD-L1 on CD90+ (myo-)fibroblasts in Crohn's disease and regulate Th1/Th17 cell responses.,International Immunology

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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

Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USA.
Institute of Translational Science, University of Texas Medical Branch, Galveston, TX, USA.
Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.
Department of Medicine at PennState Health Milton S. Hershey Medical Center, Hershey, PA, USA.
Department of Pathology, University of New Mexico, Albuquerque, NM, USA.
School of Medicine, University of New Mexico, Albuquerque, NM, USA.
Department of Surgery at the University of New Mexico, Albuquerque, NM, USA.
Department of Pharmacology & Toxicology, University of Texas Medical Branch, Galveston, TX, USA.
Microbiology and Immunology at the University of Texas Medical Branch, Galveston, TX, USA.
Department of Biochemistry and Molecular Biology, PennState Health Milton S. Hershey Medical Center, Hershey, PA, USA.
Department of Colorectal Surgery at PennState Health Milton S. Hershey Medical Center, Hershey, PA, USA.

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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