Acute GVHD results in a severe DC defect that prevents T-cell priming and leads to fulminant cytomegalovirus disease in mice

• Published in: Blood 2015-09, Vol.126 (12), p.1503-1514
• Main Authors: Wikstrom, Matthew E., Fleming, Peter, Kuns, Rachel D., Schuster, Iona S., Voigt, Valentina, Miller, Gregory, Clouston, Andrew D., Tey, Siok-Keen, Andoniou, Christopher E., Hill, Geoffrey R., Degli-Esposti, Mariapia A.
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Animals; Bone Marrow Transplantation - adverse effects; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - pathology; CD8-Positive T-Lymphocytes - virology; Cells, Cultured; Cytomegalovirus - immunology; Cytomegalovirus - isolation & purification; Cytomegalovirus Infections - etiology; Cytomegalovirus Infections - immunology; Cytomegalovirus Infections - pathology; Cytomegalovirus Infections - therapy; Dendritic Cells - immunology; Dendritic Cells - pathology; Dendritic Cells - virology; Female; Graft vs Host Disease - complications; Graft vs Host Disease - immunology; Graft vs Host Disease - pathology; Graft vs Host Disease - therapy; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2015-01-622837

Viral infection is a common, life-threatening complication after allogeneic bone marrow transplantation (BMT), particularly in the presence of graft-versus-host disease (GVHD). Using cytomegalovirus (CMV) as the prototypic pathogen, we have delineated the mechanisms responsible for the inability to mount protective antiviral responses in this setting. Although CMV infection was self-limiting after syngeneic BMT, in the presence of GVHD after allogeneic BMT, CMV induced a striking cytopathy resulting in universal mortality in conjunction with a fulminant necrotizing hepatitis. Critically, GVHD induced a profound dendritic cell (DC) defect that led to a failure in the generation of CMV-specific CD8+ T-cell responses. This was accompanied by a defect in antiviral CD8+ T cells. In combination, these defects dramatically limited antiviral T-cell responses. The transfer of virus-specific cells circumvented the DC defects and provided protective immunity, despite concurrent GVHD. These data demonstrate the importance of avoiding GVHD when reconstructing antiviral immunity after BMT, and highlight the mechanisms by which the adoptive transfer of virus-specific T cells overcome the endogenous defects in priming invoked by GVHD. •GVHD elicits profound defects in DCs that prevent the priming of virus-specific T cells.•Transfer of polyclonal T cells from immune donors at transplant provides effective antiviral immunity despite the presence of active GVHD.