4-1BB (CD137) signals depend upon CD28 signals in alloimmune responses.
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.
Lee
Eun-A
EA
The Immunomodulation Research Center, University of Ulsan, Ulsan 680-742, Korea.
Kim
Jeong-Eun
JE
Seo
Jae Hee
JH
Kwon
Byoung Se
BS
Nam
Seok Hyun
SH
Kwon
Byungsuk
B
Cho
Hong Rae
HR
D053330:4-1BB Ligand / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000276:immunology; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D003601:Cytotoxicity Tests, Immunologic; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology; D007519:Isoantigens / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000276:immunology*; D014184:Transplantation, Homologous / Q000276:immunology
D053330:4-1BB Ligand; D000906:Antibodies; D018106:CD28 Antigens; D007519:Isoantigens