Different costimulation signals used by CD4+ and CD8+ cells that independently initiate rejection of allogenic hepatocytes in mice

Authors

  • Donghong Gao,

    1. The Ohio State University College of Medicine, Department of Surgery, Columbus, Ohio
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  • Jiashun Li,

    1. The Ohio State University College of Medicine, Department of Surgery, Columbus, Ohio
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  • Charles G. Orosz,

    1. The Ohio State University College of Medicine, Department of Surgery, Columbus, Ohio
    2. the Comprehensive Cancer Center, Columbus, Ohio
    3. The Ohio State University, Departments of Pathology and Molecular Virology, Immunology and Medical Genetics, Columbus, Ohio
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  • Ginny L. Bumgardner

    Corresponding author
    1. The Ohio State University College of Medicine, Department of Surgery, Columbus, Ohio
    2. the Comprehensive Cancer Center, Columbus, Ohio
    • Ohio State University and Medical Center, 1654 Upham Drive, 373 Means Hall, Columbus, OH 43210
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Abstract

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-2q) hepatocytes occurred by day 10 posttransplant in untreated CD8 or CD4 KO (H-2b) 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-2b) 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.

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