PD-1-PD-L1 pathway is involved in suppressing alloreactivity of heart infiltrating t cells during murine gvhd across minor histocompatibility antigen barriers.
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-2) model, GVHD was induced by transplantation of 1x10 bone marrow and 1x10 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, CD8alpha+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.
Children's Hospital, University of Tuebingen, Tuebingen, Germany. knschilb@med.uni-tuebingen.de
Karin
K
Schilbach
Judith
J
Schick
Manfred
M
Wehrmann
Gernot
G
Wollny
Perikles
P
Simon
Simon
S
Perikles
Paul G
PG
Schlegel
Matthias
M
Eyrich
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000235:genetics; D000954:Antigens, Surface / Q000096:biosynthesis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics*; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000235:genetics*; D060890:B7-H1 Antigen; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D060908:CTLA-4 Antigen; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006086:Graft vs Host Disease / Q000150:complications / Q000276:immunology / Q000473:pathology; D006331:Heart Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D007082:Ileum / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D015778:Minor Histocompatibility Antigens / Q000276:immunology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000235:genetics*; D016133:Polymerase Chain Reaction; D061026:Programmed Cell Death 1 Receptor; D012333:RNA, Messenger / Q000235:genetics; D014182:Transplantation, Autologous
D015703:Antigens, CD; D000943:Antigens, Differentiation; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D051792:Basic Helix-Loop-Helix Proteins; D060908:CTLA-4 Antigen; D008562:Membrane Glycoproteins; D015778:Minor Histocompatibility Antigens; D010455:Peptides; D061026:Programmed Cell Death 1 Receptor; D012333:RNA, Messenger; C498919:Cd274 protein, mouse; C556707:Ctla4 protein, mouse; C095572:Hand1 protein, mouse; C491383:Pdcd1 protein, mouse