Divergent Function of Programmed Death-Ligand 1 in Donor Tissue versus Recipient Immune System in a Murine Model of Bronchiolitis Obliterans
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Divergent Function of Programmed Death-Ligand 1 in Donor Tissue versus Recipient Immune System in a Murine Model of Bronchiolitis Obliterans. / Schütte-Nütgen, Katharina; Boenisch, Olaf; Harrach, Hakima; Casey, Alicia; Guleria, Indira; Najafian, Nader; Sayegh, Mohamed H; Gerard, Craig J; Subramaniam, Meera.
in: AM J PATHOL, Jahrgang 187, Nr. 6, 06.2017, S. 1368-1379.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Divergent Function of Programmed Death-Ligand 1 in Donor Tissue versus Recipient Immune System in a Murine Model of Bronchiolitis Obliterans
AU - Schütte-Nütgen, Katharina
AU - Boenisch, Olaf
AU - Harrach, Hakima
AU - Casey, Alicia
AU - Guleria, Indira
AU - Najafian, Nader
AU - Sayegh, Mohamed H
AU - Gerard, Craig J
AU - Subramaniam, Meera
N1 - Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
PY - 2017/6
Y1 - 2017/6
N2 - Costimulatory molecules, such as the programmed death ligand (PD-L1), might exert differential effects on T-cell function, depending on the clinical setting and/or immunological environment. Given the impact of T cells on bronchiolitis obliterans (BO) in lung transplantation, we used an established tracheal transplant model inducing BO-like lesions to investigate the impact of PD-L1 on alloimmune responses and histopathological outcome in BO. In contrast to other transplant models in which PD-L1 generally shows protective functions, we demonstrated that PD-L1 has divergent effects depending on its location in donor versus recipient tissue. Although PD-L1 deficiency in donor tissue worsened histopathological outcome, and increased systemic inflammatory response, recipient PD-L1 deficiency induced opposite effects. Mechanistic studies revealed PD-L1-deficient recipients were hyporesponsive toward alloantigen, despite increased numbers of CD8+ effector T cells. The function of PD-L1 on T cells after unspecific stimulation was dependent on both cell type and strength of stimulation. This novel function of recipient PD-L1 may result from the high degree of T-cell activation within the highly immunogenic milieu of the transplanted tissue. In this model, both decreased T-cell alloimmune responses and the reduction of BO in PD-L1-deficient recipients suggest a potential therapeutic role of selectively blocking PD-L1 in the recipient. Further investigation is warranted to determine the impact of this finding embedded in the complex pathophysiological context of BO.
AB - Costimulatory molecules, such as the programmed death ligand (PD-L1), might exert differential effects on T-cell function, depending on the clinical setting and/or immunological environment. Given the impact of T cells on bronchiolitis obliterans (BO) in lung transplantation, we used an established tracheal transplant model inducing BO-like lesions to investigate the impact of PD-L1 on alloimmune responses and histopathological outcome in BO. In contrast to other transplant models in which PD-L1 generally shows protective functions, we demonstrated that PD-L1 has divergent effects depending on its location in donor versus recipient tissue. Although PD-L1 deficiency in donor tissue worsened histopathological outcome, and increased systemic inflammatory response, recipient PD-L1 deficiency induced opposite effects. Mechanistic studies revealed PD-L1-deficient recipients were hyporesponsive toward alloantigen, despite increased numbers of CD8+ effector T cells. The function of PD-L1 on T cells after unspecific stimulation was dependent on both cell type and strength of stimulation. This novel function of recipient PD-L1 may result from the high degree of T-cell activation within the highly immunogenic milieu of the transplanted tissue. In this model, both decreased T-cell alloimmune responses and the reduction of BO in PD-L1-deficient recipients suggest a potential therapeutic role of selectively blocking PD-L1 in the recipient. Further investigation is warranted to determine the impact of this finding embedded in the complex pathophysiological context of BO.
KW - Animals
KW - B7-H1 Antigen
KW - Bronchiolitis Obliterans
KW - CD4-Positive T-Lymphocytes
KW - CD8-Positive T-Lymphocytes
KW - Disease Models, Animal
KW - Epithelial Cells
KW - Graft Survival
KW - Immune Tolerance
KW - Immunity, Cellular
KW - Isoantigens
KW - Lymphocyte Activation
KW - Mice, Inbred BALB C
KW - Mice, Inbred C57BL
KW - Tissue Donors
KW - Trachea
KW - Transplantation Immunology
KW - Up-Regulation
KW - Journal Article
U2 - 10.1016/j.ajpath.2017.02.007
DO - 10.1016/j.ajpath.2017.02.007
M3 - SCORING: Journal article
C2 - 28427861
VL - 187
SP - 1368
EP - 1379
JO - AM J PATHOL
JF - AM J PATHOL
SN - 0002-9440
IS - 6
ER -