Different costimulatory and growth factor requirements for CD4+ and CD8+ T cell-mediated rejection.
Costimulatory signals and growth factor signals play a key role in commanding T cell activation and T cell effector function. However, how costimulatory signals and growth factor signals interact and integrate into the activation program of CD4(+) and CD8(+) T cells during the allograft response remains poorly defined. In the present study we found that either CD4- or CD8-deficient mice can vigorously reject the skin allografts. Blocking rapamycin-sensitive growth factor signals produced long term skin allograft survival in CD4-deficient mice (mean survival time, >120 days), but not in CD8-deficient mice (mean survival time, 20 days). Analysis of CFSE-labeled cells proliferating in the allogeneic hosts revealed that clonal expansion of CD4(+) T cells in vivo was more resistant to growth factor blockade than that of CD8(+) T cells. However, blockade or genetic absence of CD28/CD154 costimulatory molecules rendered CD4(+) T cell-mediated rejection sensitive to rapamycin, and long term skin allograft survival can be readily induced by rapamycin in the absence of CD28/CD154 signals (>100 days). Furthermore, blocking OX40 costimulation induced long term skin allograft survival in CD4-deficient mice and CD8-deficient mice when both CD28 and CD154 were transiently blocked. We conclude that CD4(+) and CD8(+) T cells exhibit distinct sensitivity to growth factor blockade in transplant rejection, and CD28/CD154-independent rejection is sensitive to rapamycin and appears to be supported by OX40 costimulation.
Vu
Minh Diem
MD
Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
Amanullah
Farhana
F
Li
Yongsheng
Y
Demirci
Gulcin
G
Sayegh
Mohamed H
MH
Li
Xian Chang
XC
D000818:Animals; D018106:CD28 Antigens / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D023201:CD40 Ligand / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D006084:Graft Rejection; D006133:Growth Substances / Q000502:physiology*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D016038:Skin Transplantation / Q000276:immunology*; D014184:Transplantation, Homologous
D018106:CD28 Antigens; D006133:Growth Substances; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; C505717:Tnfrsf4 protein, mouse; D023201:CD40 Ligand; D020123:Sirolimus