PD-1–PD-L1 Pathway Is Involved in Suppressing Alloreactivity of Heart Infiltrating T Cells During Murine GVHD Across Minor Histocompatibility Antigen Barriers

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Background.Graft-versus-host disease (GVHD) is still a major cause of morbidity and mortality after allogeneic stem cell transplantation. GVHD mainly affects skin, liver, and intestine, whereas other organs usually are spared. In the present study, we wanted to investigate whether local regulatory T cells (Treg) or differential expression of immunomodulatory molecules contribute to organ specificity of GVHD.Methods.In a murine B10.D2->BALB/c (both H-2d) model, GVHD was induced by transplantation of 1×107 bone marrow and 1×108 spleen cells. We compared expression of T-cell and dendritic cell markers, CD40-CD40L, various B7 family members, FoxP3, and Th1/Th2 cytokines between ileum (GVHD-target organ) and heart (nontarget organ).Results.GVHD was documented by an increase of CD4+ T cells with accompanying tissue destruction in ileum but not in heart. We found a significantly increased expression of PD-L1 in heart on day 14 and 21 as well as of CTLA-4 on day 21 after transplantation, whereas all other molecules were not different between heart and ileum. In heart, PD-L1 was expressed on lymphoid cells, endothelial cells, CD8α+CD11c+DCs, and up-regulated during GVHD. In contrast, in the ileum only endothelial cells stained weekly positive for PD-L1. Furthermore, we could not find any evidence for the presence of Tregs in the heart.Conclusions.Our data indicate that immunomodulatory molecules such as PD-L1 rather than Tregs play pivotal roles in the tissue-specific regulation of alloresponses. Further studies are needed to refine the significance of the PD-L1 pathway in GVHD and its versatility for therapeutic intervention.

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