TY - JOUR
T1 - Acute GVHD results in a severe DC defect that prevents T-cell priming and leads to fulminant cytomegalovirus disease in mice
AU - Wikstrom, Matthew E.
AU - Fleming, Peter
AU - Kuns, Rachel D.
AU - Schuster, Iona S.
AU - Voigt, Valentina
AU - Miller, Gregory
AU - Clouston, Andrew D.
AU - Tey, Siok Keen
AU - Andoniou, Christopher E.
AU - Hill, Geoffrey R.
AU - Degli-Esposti, Mariapia A.
PY - 2015/9/17
Y1 - 2015/9/17
N2 - 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 tomount 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.
AB - 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 tomount 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.
UR - http://www.scopus.com/inward/record.url?scp=84942907584&partnerID=8YFLogxK
U2 - 10.1182/blood-2015-01-622837
DO - 10.1182/blood-2015-01-622837
M3 - Article
C2 - 26130706
AN - SCOPUS:84942907584
SN - 0006-4971
VL - 126
SP - 1503
EP - 1514
JO - Blood
JF - Blood
IS - 12
ER -