Divergent Function of Programmed Death-Ligand 1 in Donor Tissue versus Recipient Immune System in a Murine Model of Bronchiolitis Obliterans

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 -