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.
Koji Kishimoto, Victor M. Dong, Shohreh Issazadeh, Eugenia V. Fedoseyeva, Ana Maria Waaga, Akira Yamada, Masayuki Sho, Gilles Benichou, Hugh Auchincloss Jr., Michael J. Grusby, Samia J. Khoury, Mohamed H. Sayegh