CD28-independent costimulation of T cells in alloimmune responses.
T cell costimulation by B7 molecules plays an important role in the regulation of alloimmune responses. Although both B7-1 and B7-2 bind CD28 and CTLA-4 on T cells, the role of B7-1 and B7-2 signaling through CTLA-4 in regulating alloimmune responses is incompletely understood. To address this question, we transplanted CD28-deficient mice with fully allogeneic vascularized cardiac allografts and studied the effect of selective blockade of B7-1 or B7-2. These mice reject their grafts by a mechanism that involves both CD4(+) and CD8(+) T cells. Blockade of CTLA-4 or B7-1 significantly accelerated graft rejection. In contrast, B7-2 blockade significantly prolonged allograft survival and, unexpectedly, reversed the acceleration of graft rejection caused by CTLA-4 blockade. Furthermore, B7-2 blockade prolonged graft survival in recipients that were both CD28 and CTLA-4 deficient. Our data indicate that B7-1 is the dominant ligand for CTLA-4-mediated down-regulation of alloimmune responses in vivo and suggest that B7-2 has an additional receptor other than CD28 and CTLA-4 to provide a positive costimulatory signal for T cells.
Yamada
A
A
Laboratory of Immunogenetics and Transplantation and Immunology Research Division, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Kishimoto
K
K
Dong
V M
VM
Sho
M
M
Salama
A D
AD
Anosova
N G
NG
Benichou
G
G
Mandelbrot
D A
DA
Sharpe
A H
AH
Turka
L A
LA
Auchincloss
H
H
Sayegh
M H
MH
D000069594:Abatacept; D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000008:administration & dosage / Q000276:immunology; D018122:B7-1 Antigen / Q000008:administration & dosage / Q000276:immunology; D018106:CD28 Antigens / Q000235:genetics / Q000502:physiology*; D060908:CTLA-4 Antigen; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology; D007106:Immune Sera / Q000008:administration & dosage; D018796:Immunoconjugates; D007274:Injections, Intraperitoneal; D007519:Isoantigens / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D019138:Antibodies, Blocking; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D007106:Immune Sera; D018796:Immunoconjugates; D007519:Isoantigens; D011948:Receptors, Antigen, T-Cell; D000069594:Abatacept