The role of CD154-CD40 versus CD28-B7 costimulatory pathways in regulating allogeneic Th1 and Th2 responses in vivo.
We used signal transducer and activator of transcription 4 (STAT4) and STAT6 gene knockout (-/-) mice as recipients of fully mismatched cardiac allografts to study the role of T-cell costimulatory pathways in regulating allogeneic T-helper 1 (Th1) versus Th2 responses in vivo. STAT4(-/-) mice have impaired Th1 responses, whereas STAT6(-/-) mice do not generate normal Th2 responses. Cardiac allografts from C57BL/6 mice were transplanted into normal wild-type (WT), STAT4(-/-), and STAT6(-/-) BALB/c recipients. STAT4(-/-) and STAT6(-/-) mice rejected their grafts with the same tempo as untreated WT recipients. CD28-B7 blockade by a single injection of CTLA4Ig induced long-term engraftment and donor-specific tolerance in all three groups of recipients. CD154 blockade by a single injection of MR1 was effective in prolonging allograft survival and inducing tolerance in STAT4(-/-) mice but was only marginally effective in STAT6(-/-) recipients and WT controls. In addition, a similar protocol of MR1 was ineffective in prolonging graft survival in CD28(-/-) BALB/c recipients, suggesting that the lack of efficacy seen in WT and STAT6(-/-) mice is not due to the presence of a functional CD28-B7 pathway. Furthermore, there was a similar differential effect of CD28-B7 versus CD154-CD40 blockade in inhibiting immune responses in animals immunized with ovalbumin and complete Freund's adjuvant. These novel data indicate that Th1 and Th2 cells are differentially regulated by CD28-B7 versus CD154-CD40 costimulation pathways in vivo and may have potential implications for the development of therapeutic strategies such as T-cell costimulatory blockade in humans.
Kishimoto
K
K
Laboratory of Immunogenetics and Transplantation, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Dong
V M
VM
Issazadeh
S
S
Fedoseyeva
E V
EV
Waaga
A M
AM
Yamada
A
A
Sho
M
M
Benichou
G
G
Auchincloss
H
H
Grusby
M J
MJ
Khoury
S J
SJ
Sayegh
M H
MH
D000818:Animals; D018122:B7-1 Antigen / Q000502:physiology*; D018106:CD28 Antigens / Q000502:physiology*; D019013:CD40 Antigens / Q000502:physiology*; D023201:CD40 Ligand; D016207:Cytokines / Q000502:physiology; D004268:DNA-Binding Proteins / Q000502:physiology; D006084:Graft Rejection; D016027:Heart Transplantation; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000502:physiology*; D015534:Trans-Activators / Q000502:physiology; D014184:Transplantation, Homologous
D018122:B7-1 Antigen; D018106:CD28 Antigens; D019013:CD40 Antigens; D016207:Cytokines; D004268:DNA-Binding Proteins; D008562:Membrane Glycoproteins; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; C494091:Stat4 protein, mouse; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D023201:CD40 Ligand