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, 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.

    Original languageEnglish (US)
    Pages (from-to)57-68
    Number of pages12
    JournalInternational immunology
    Volume32
    Issue number1
    DOIs
    StatePublished - Jan 9 2020

    Fingerprint

    Th17 Cells
    Th1 Cells
    Matrix Metalloproteinases
    Crohn Disease
    Fibroblasts
    Membranes
    Matrix Metalloproteinase 10
    Matrix Metalloproteinase 7
    Matrix Metalloproteinase Inhibitors
    Neutralizing Antibodies
    T-Lymphocytes
    Mucosal Immunity
    Matrix Metalloproteinase 9
    Intestinal Mucosa
    Coculture Techniques
    Ulcerative Colitis

    Keywords

    • Crohn’s disease
    • matrix metalloproteinases
    • membrane-bound and soluble PD-L1
    • myo-/fibroblasts

    ASJC Scopus subject areas

    • Immunology and Allergy
    • Immunology

    Cite this

    Matrix metalloproteinases cleave membrane-bound PD-L1 on CD90+ (myo-)fibroblasts in Crohn's disease and regulate Th1/Th17 cell responses. / Aguirre, Jose E.; Beswick, Ellen J.; Grim, Carl; Uribe, Gabriela; Tafoya, Marissa; Chacon Palma, Gabriela; Samedi, Von; McKee, Rohini; Villeger, Romain; Fofanov, Yuriy; Cong, Yingzi; Yochum, Gregory; Koltun, Walter; Powell, Don; Pinchuk, Irina V.

    In: International immunology, Vol. 32, No. 1, 09.01.2020, p. 57-68.

    Research output: Contribution to journalArticle

    Aguirre, JE, Beswick, EJ, Grim, C, Uribe, G, Tafoya, M, Chacon Palma, G, Samedi, V, McKee, R, Villeger, R, Fofanov, Y, Cong, Y, Yochum, G, Koltun, W, Powell, D & Pinchuk, IV 2020, 'Matrix metalloproteinases cleave membrane-bound PD-L1 on CD90+ (myo-)fibroblasts in Crohn's disease and regulate Th1/Th17 cell responses', International immunology, vol. 32, no. 1, pp. 57-68. https://doi.org/10.1093/intimm/dxz060
    Aguirre, Jose E. ; Beswick, Ellen J. ; Grim, Carl ; Uribe, Gabriela ; Tafoya, Marissa ; Chacon Palma, Gabriela ; Samedi, Von ; McKee, Rohini ; Villeger, Romain ; Fofanov, Yuriy ; Cong, Yingzi ; Yochum, Gregory ; Koltun, Walter ; Powell, Don ; Pinchuk, Irina V. / Matrix metalloproteinases cleave membrane-bound PD-L1 on CD90+ (myo-)fibroblasts in Crohn's disease and regulate Th1/Th17 cell responses. In: International immunology. 2020 ; Vol. 32, No. 1. pp. 57-68.
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    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, 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.",
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    AU - Grim, Carl

    AU - Uribe, Gabriela

    AU - Tafoya, Marissa

    AU - Chacon Palma, Gabriela

    AU - Samedi, Von

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    AU - Villeger, Romain

    AU - Fofanov, Yuriy

    AU - Cong, Yingzi

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    AU - Koltun, Walter

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