The role of CD154-CD40 versus CD28-B7 costimulatory pathways in regulating allogeneic Th1 and Th2 responses in vivo

J Clin Invest. 2000 Jul;106(1):63-72. doi: 10.1172/JCI9586.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • B7-1 Antigen / physiology*
  • CD28 Antigens / physiology*
  • CD40 Antigens / physiology*
  • CD40 Ligand
  • Cytokines / physiology
  • DNA-Binding Proteins / physiology
  • Graft Rejection
  • Heart Transplantation
  • Membrane Glycoproteins / physiology*
  • Mice
  • Mice, Inbred Strains
  • STAT4 Transcription Factor
  • STAT6 Transcription Factor
  • Th1 Cells / immunology*
  • Th2 Cells / physiology*
  • Trans-Activators / physiology
  • Transplantation, Homologous


  • B7-1 Antigen
  • CD28 Antigens
  • CD40 Antigens
  • Cytokines
  • DNA-Binding Proteins
  • Membrane Glycoproteins
  • STAT4 Transcription Factor
  • STAT6 Transcription Factor
  • Stat4 protein, mouse
  • Stat6 protein, mouse
  • Trans-Activators
  • CD40 Ligand