B7-H3 expression in donor T cells and host cells negatively regulates acute graft-versus-host disease lethality

• Published in: Blood 2015-05, Vol.125 (21), p.3335-3346
• Main Authors: Veenstra, Rachelle G., Flynn, Ryan, Kreymborg, Katharina, McDonald-Hyman, Cameron, Saha, Asim, Taylor, Patricia A., Osborn, Mark J., Panoskaltsis-Mortari, Angela, Schmitt-Graeff, Annette, Lieberknecht, Elisabeth, Murphy, William J., Serody, Jonathan S., Munn, David H., Freeman, Gordon J., Allison, James P., Mak, Tak W., van den Brink, Marcel, Zeiser, Robert, Blazar, Bruce R.
• Format: Article
• Language: English
• Subjects: Allografts; Animals; B7 Antigens - immunology; Bone Marrow Transplantation - adverse effects; Flow Cytometry; Graft vs Host Disease - immunology; Humans; Immunohistochemistry; Mice; Polymerase Chain Reaction; T-Lymphocytes - immunology; Transplantation
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2014-09-603357

Members of the B7 family have been shown to be important for regulating immune responses by providing either positive or negative costimulatory signals. The function of B7-H3 has been controversial. We show that B7-H3 is upregulated in graft-versus-host disease (GVHD) target organs, including the colon, liver, and lung. Infusion of allogeneic donor T cells into B7-H3−/− vs wild-type (WT) recipients resulted in increased GVHD lethality associated with increased T-cell proliferation, colonic inflammatory cytokines, and destruction of epithelial barriers. Allogeneic B7-H3−/− vs WT donor T cells also had increased T-cell proliferation and GVHD lethality associated with increased proliferation and cytokine secretion in the spleen, intraepithelial lymphocyte inflammatory cytokines, and intestinal permeability. Both resting and activated regulatory T cells (Tregs) lack B7-H3 messenger RNA. Consistent with these data, GVHD was augmented in recipients of B7-H3−/− Treg-depleted grafts. In two delayed lymphocyte infusion (DLI) models, T cells lacking B7-H3 are capable of providing graft-versus-leukemia (GVL) effects. We conclude that B7-H3 is responsible for providing a negative costimulatory signal. Our studies provide support for developing and testing new therapies directed toward the B7-H3 pathway, including approaches to augment host B7-H3 early after bone marrow transplantation to prevent GVHD and to develop potent antagonistic antibodies later after transplant to facilitate DLI-mediated GVL without GVHD complications. •Absence of B7-H3 expression in allogeneic recipients or on allogeneic donor T cells leads to accelerated GVHD lethality.•Increased GVHD lethality is a result of increased T-cell proliferation, colon inflammatory cytokines, and intestinal permeability.