Viral infection abrogates CD8(+) T-cell deletion induced by costimulation blockade.
BACKGROUND
Treatment with a single donor-specific transfusion (DST) plus a brief course of anti-CD154 monoclonal antibody (mAb) prolongs skin allograft survival in mice. It is known that prolongation of allograft survival by this method depends in part on deletion of alloreactive CD8(+) T cells at the time of tolerance induction. Recent data suggest that infection with lymphocytic choriomeningitis virus (LCMV) abrogates the ability of this protocol to prolong graft survival.


METHODS
To study the mechanism by which viral infection abrogates allograft survival, we determined (1) the fate of tracer populations of alloreactive transgenic CD8(+) T cells and (2) the duration of skin allograft survival following treatment with DST and anti-CD154 mAb in the presence or absence of LCMV infection.


RESULTS
We confirmed that treatment of uninfected mice with DST and anti-CD154 mAb leads to the deletion of alloreactive CD8(+) T cells and is associated with prolongation of skin allograft survival. In contrast, treatment with DST and anti-CD154 mAb in the presence of intercurrent LCMV infection was associated with the failure to delete alloreactive CD8(+) T cells and with the rapid rejection of skin allografts. The number of alloreactive CD8(+) cells actually increased significantly, and the cells acquired an activated phenotype.


CONCLUSIONS
Interference with the deletion of alloreactive CD8(+) T cells mediated by DST and anti-CD154 mAb may in part be the mechanism by which viral infection abrogates transplantation tolerance induction.
Turgeon
N A
NA
Departments of Medicine, Pathology, and Surgery, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Iwakoshi
N N
NN
Phillips
N E
NE
Meyers
W C
WC
Welsh
R M
RM
Greiner
D L
DL
Mordes
J P
JP
Rossini
A A
AA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001803:Blood Transfusion; D023201:CD40 Ligand; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D005260:Female; D007108:Immune Tolerance; D008212:Lymphocyte Depletion; D008216:Lymphocytic Choriomeningitis / Q000276:immunology*; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D016038:Skin Transplantation / Q000276:immunology; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D008562:Membrane Glycoproteins; D023201:CD40 Ligand