Exp Mol Med.  2006 Dec;38(6):606-615.

4-1BB (CD137) signals depend upon CD28 signals in alloimmune responses

• Lee EA
• Kim JE
• Seo JH
• Kwon BS
• Nam SH
• Kwon B
• Cho HR

Abstract

Our previous study has demonstrated that there is a significant delay of Balb/c cardiac allograft rejection in the C57BL/6 4-1BB-deficient knockout recipient. In this study, we examined the effect of combined blockade of the 4-1BB and CD28 costimulatory pathways on cardiac allograft rejection in the C57BL/6-->Balb/c model. A long-term cardiac allograft survival was induced in CD28/4-1BB- deficient mice (>100 days survival in 3 of 4 mice), which was comparable with CD28-deficient mice (>100 days survival in 2 of 5 mice; P<0.2026). There was no long-term cardiac allograft survival in either wild-type (WT) or 4-1BB-deficient mice, even though 4-1BB-deficient recipients showed a significant delay of cardiac allograft rejection than WT mice. An in vitro mixed leukocyte reaction (MLR) assay showed that 4-1BB-deficient and WT mouse T cells had a similar responsiveness to allostimulation, whereas CD28- and CD28/4-1BB-deficient mouse T cells had a defective responsiveness to allostimulation. Furthermore, 4-1BB-deficient mice showed a similar CTL but an elevated Ab response against alloantigens as compared to WT mice, and the alloimmune responses of 4-1BB-deficient mice were abrogated in the CD28-deficient background. Overall, these results indicate that the CD28 costimulatory pathway plays a major role in the alloimmune response and that 4-1BB signals are dependent upon CD28 signals.

Keyword

antibody formation; antigens; CD28; CD137 antigen; graft rejection; mice; knockout

MeSH Terms

Transplantation, Homologous/immunology
Signal Transduction/*immunology
Mice, Knockout
Mice
Isoantigens/immunology
Heart Transplantation/immunology
Graft Survival/immunology
Cytotoxicity Tests, Immunologic
Antigens, CD28/genetics/*immunology/metabolism
Antibodies/immunology
Animals
4-1BB Ligand/deficiency/genetics/*immunology/metabolism