Alloantigen expression on non-hematopoietic cells reduces graft-versus-leukemia effects in mice.
Allogeneic hematopoietic stem cell transplantation (HSCT) is used effectively to treat a number of hematological malignancies. Its beneficial effects rely on donor-derived T cell-targeted leukemic cells, the so-called graft-versus-leukemia (GVL) effect. Induction of GVL is usually associated with concomitant development of graft-versus-host disease (GVHD), a major complication of allogeneic HSCT. The T cells that mediate GVL and GVHD are activated by alloantigen presented on host antigen-presenting cells of hematopoietic origin, and it is not well understood how alloantigen expression on non-hematopoietic cells affects GVL activity. Here we show, in mouse models of MHC-matched, minor histocompatibility antigen-mismatched bone marrow transplantation, that alloantigen expression on host epithelium drives donor T cells into apoptosis and dysfunction during GVHD, resulting in a loss of GVL activity. During GVHD, programmed death-1 (PD-1) and PD ligand-1 (PD-L1), molecules implicated in inducing T cell exhaustion, were upregulated on activated T cells and the target tissue, respectively, suggesting that the T cell defects driven by host epithelial alloantigen expression might be mediated by the PD-1/PD-L1 pathway. Consistent with this, blockade of PD-1/PD-L1 interactions partially restored T cell effector functions and improved GVL. These results elucidate a previously unrecognized significance of alloantigen expression on non-hematopoietic cells in GVL and suggest that separation of GVL from GVHD for more effective HSCT may be possible in human patients.
Asakura
Shoji
S
Biopathological Science, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan.
Hashimoto
Daigo
D
Takashima
Shuichiro
S
Sugiyama
Haruko
H
Maeda
Yoshinobu
Y
Akashi
Koichi
K
Tanimoto
Mitsune
M
Teshima
Takanori
T
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000637:transplantation; D016026:Bone Marrow Transplantation / Q000276:immunology; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology* / Q000473:pathology; D018380:Hematopoietic Stem Cell Transplantation; D007519:Isoantigens / Q000276:immunology; D007938:Leukemia / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation
D007519:Isoantigens; D015778:Minor Histocompatibility Antigens