Different costimulation signals used by CD4(+) and CD8(+) cells that independently initiate rejection of allogenic hepatocytes in mice.
The current study evaluated the role of CD40/CD40 ligand (CD40L) and CD28/B7 costimulation signals during alloimmune responses independently mediated by CD4(+) or CD8(+) T cells. Allogeneic hepatocytes were transplanted into CD8 or CD4 knock out (KO) mice under cover of costimulatory blockade. Rejection of FVB/N (H-2(q)) hepatocytes occurred by day 10 posttransplant in untreated CD8 or CD4 KO (H-2(b)) mice. Treatment of CD8 or CD4 KO mice with anti-CD40L monoclonal antibody (mAb; MR1) resulted in significant prolongation of hepatocyte survival indicating that CD40/CD40L interactions were critical in both CD4(+) and CD8(+) T-cell initiated hepatocyte rejection. Anti-CD40L mAb also prolonged hepatocyte survival in B-cell KO (H-2(b)) mice, indicating that the efficacy of CD40/CD40L blockade in preventing hepatocyte rejection was B-cell (and antibody) independent. In contrast, treatment with CTLA4 fusion protein (CTLA4Ig), prolonged hepatocyte survival in CD8 KO but not CD4 KO mice, showing that CD28/B7 interactions were important in CD4(+) but not CD8(+) T-cell initiated hepatocyte rejection. Under selected circumstances, such as in CD40 KO mice, both CD4(+) and CD8(+) T cells mediate hepatocyte rejection in the absence of CD40/CD40L costimulation and without a significant contribution from CD28/B7 costimulation signals. These results highlight the disparate roles of CD40/CD40L and CD28/B7 costimulation signals in CD4(+) versus CD8(+) T-cell mediated immune responses to allogeneic hepatocytes. The CD4(+) T-cell independent, CD40L-sensitive, CD28/B7-independent pathway of CD8(+) T-cell activation in response to transplantation antigens is novel.
Gao
D
D
The Ohio State University College of Medicine, Department of Surgery, Columbus, Ohio, USA.
Li
J
J
Orosz
C G
CG
Bumgardner
G L
GL
D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000494:pharmacology; D001402:B-Lymphocytes / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D019013:CD40 Antigens / Q000235:genetics / Q000502:physiology; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D060908:CTLA-4 Antigen; D006084:Graft Rejection / Q000209:etiology*; D006085:Graft Survival / Q000187:drug effects; D022781:Hepatocytes / Q000502:physiology / Q000637:transplantation*; D006968:Hypersensitivity, Delayed / Q000276:immunology; D018796:Immunoconjugates; D007518:Isoantibodies / Q000032:analysis; D008099:Liver / Q000166:cytology / Q000502:physiology; D008285:Major Histocompatibility Complex / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics / Q000502:physiology; D013154:Spleen / Q000166:cytology / Q000502:physiology; D014019:Tissue Donors; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D019013:CD40 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007518:Isoantibodies; D023201:CD40 Ligand; D000069594:Abatacept