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

Jose E. Aguirre, Ellen J. Beswick, Carl Grim, Gabriela Uribe, Marissa Tafoya, Gabriela Chacon Palma, Von Samedi, Rohini McKee, Romain Villeger, Yuriy Fofanov, Yingzi Cong, Gregory Yochum, Walter Koltun, Don Powell, Irina V. Pinchuk

Research output: Contribution to journalArticle

Abstract

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, mPDL1-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.

Original languageEnglish (US)
Pages (from-to)57-68
Number of pages12
JournalInternational immunology
Volume32
Issue number1
DOIs
StatePublished - Jan 1 2020

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Keywords

  • Crohn’s disease
  • Matrix metalloproteinases
  • Membrane-bound and soluble PD-L1
  • Myo-/fibroblasts

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Aguirre, J. E., Beswick, E. J., Grim, C., Uribe, G., Tafoya, M., Palma, G. C., Samedi, V., McKee, R., Villeger, R., Fofanov, Y., Cong, Y., Yochum, G., Koltun, W., Powell, D., & Pinchuk, I. V. (2020). Matrix metalloproteinases cleave membrane-bound PD-L1 on CD90+ (myo-)fibroblasts in Crohn’s disease and regulate Th1/Th17 cell responses. International immunology, 32(1), 57-68. https://doi.org/10.1093/intimm/dxz060