B7-dependent T-cell costimulation in mice lacking CD28 and CTLA4.
To examine whether B7 costimulation can be mediated by a molecule on T cells that is neither CD28 nor CTLA4, we generated mice lacking both of these receptors. CD28/CTLA4(-/-) mice resemble CD28(-/-) mice in having decreased expression of T-cell activation markers in vivo and decreased T-cell proliferation in vitro, as compared with wild-type mice. Using multiple approaches, we find B7-dependent costimulation in CD28/CTLA4(-/-) mice. The proliferation of CD28/CTLA4(-/-) T cells is inhibited by CTLA4-Ig and by the use of antigen-presenting cells lacking both B7-1 and B7-2. CD28/CTLA4(-/-) T-cell proliferation is increased by exposure to Chinese hamster ovary cells transfected with B7-1 or B7-2. Finally, administration of CTLA4-Ig to CD28/CTLA4(-/-) cardiac allograft recipients significantly prolongs graft survival. These data support the existence of an additional receptor for B7 molecules that is neither CD28 nor CTLA4.
Mandelbrot
D A
DA
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Oosterwegel
M A
MA
Shimizu
K
K
Yamada
A
A
Freeman
G J
GJ
Mitchell
R N
RN
Sayegh
M H
MH
Sharpe
A H
AH
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology*; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology*; D016466:CHO Cells; D060908:CTLA-4 Antigen; D002455:Cell Division; D006224:Cricetinae; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation; D018796:Immunoconjugates; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000096:biosynthesis; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C497965:Cd86 protein, mouse; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D008562:Membrane Glycoproteins; D000069594:Abatacept; D007371:Interferon-gamma