Impaired alloantigen-mediated T cell apoptosis and failure to induce long-term allograft survival in IL-2-deficient mice.
We examined whether IL-2 regulates alloimmune responses by studying allograft survival in wild-type (IL-2+/+) and IL-2 gene-knockout (IL-2-/-) mice. The acute rejection of vascularized, cardiac allografts and the generation of allospecific CTLs were not impaired in the absence of IL-2. In contrast, blocking the B7-CD28 T cell costimulation pathway with CTLA4Ig induced long-term allograft survival (> 100 days) in IL-2+/+ recipients but failed to do so in IL-2-/- mice or in wild-type mice that had been treated with IL-2-neutralizing Ab around the time of transplantation. Allografts rejected by IL-2-/- recipients exhibited extensive mononuclear cell infiltrates despite CTLA4Ig administration. In vivo allostimulation in the absence of IL-2 led to exaggerated T lymphocyte proliferation and impaired apoptosis of activated T cells in untreated and CTLA4Ig-treated mice. These findings indicate that endogenous IL-2 is required for the induction of long-term allograft survival, and that IL-2 regulates alloimmune responses by preparing activated T lymphocytes for alloantigen-induced apoptosis.
The Carlos and Marguerite Mason Transplantation Research Center, Emory University and Veterans Affairs Medical Center, Atlanta, GA 30033, USA.
Z
Z
Dai
B T
BT
Konieczny
F K
FK
Baddoura
F G
FG
Lakkis
D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000276:immunology*; D003326:Coronary Circulation / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D006085:Graft Survival / Q000187:drug effects / Q000235:genetics* / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology / Q000473:pathology; D007376:Interleukin-2 / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D007519:Isoantigens / Q000502:physiology*; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D016207:Cytokines; D007376:Interleukin-2; D007519:Isoantigens; D012333:RNA, Messenger