Immunoregulatory role of CD8alpha in the veto effect.

Academic Article

Abstract

  • BACKGROUND: Allogeneic bone marrow cell (allo-BMC) infusion induces tolerance to incompatible renal allografts in rhesus macaques after depletion of peripheral T lymphocytes with cytolytic anti-T cell antibodies. The tolerogenic effect of allo-BMC, ascribed to a veto mechanism, associates with specific functional deletion of antidonor cytotoxic T lymphocyte precursor (CTLp), and is dependent on a CD8+ donor BMC subset. In previous studies, the CD8 molecule was implicated by loss of suppression after blocking interaction between CD8 on allo-BMC and major histocompatibility complex class Ialpha3 domain on CTLp. CD8 cross-linking on BMC induced secretion of active transforming growth factor-beta1 (TGF-beta1), suggesting a regulatory mechanism(s) operating via a CD8-mediated signaling pathway. METHODS: CD8 on rhesus cells was cross-linked using IgG-conjugated beads, and TGF-beta1 mRNA and protein were quantified. CD8+ cells were tested for veto activity by mixed lymphocyte reaction (MLR)-induced cell-mediated lymphocytotoxicity (CML) assay. Activated rhesus T cells exposed to TGF-beta1 were examined for apoptosis by TdT-mediated end-labeling and annexin staining. RESULTS: CD8 cross-linking induces accumulation of TGF-beta1 mRNA and protein. Both CD3- CD8+CD16+ and CD3+ CD8+CD16- subsets of allo-BMC up-regulate TGF-beta1 mRNA after CD8 cross-linking, and exhibit veto activity. The CD3-CD8+CD16+ subset expresses more TGF-beta1 mRNA and increased veto activity at low BMC/CTLp ratios. Exposure of activated T cells to TGF-beta1 induces apoptosis. CONCLUSIONS: CD8+ allo-BMC are enriched for veto activity and activation via CD8 induces TGF-beta1 mRNA and protein accumulation. These results agree with the hypothesis that paracrine TGF-beta1 may be involved in peripheral deletion of alloreactive CTLp by CD8+ allo-BMC. We suggest that TGF-beta1 overexpression by donor lymphohematopoietic cells may enhance tolerance induction.
  • Authors

    Published In

  • Transplantation  Journal
  • Keywords

  • Animals, Bone Marrow Cells, Bone Marrow Transplantation, CD8 Antigens, CD8-Positive T-Lymphocytes, Cells, Cultured, Cross-Linking Reagents, DNA Fragmentation, Immune Tolerance, Immunosuppression, Lymphocyte Depletion, Lymphocyte Transfusion, Macaca mulatta, Major Histocompatibility Complex, Protein Biosynthesis, Receptors, IgG, Reverse Transcriptase Polymerase Chain Reaction, T-Lymphocyte Subsets, T-Lymphocytes, Transcription, Genetic, Transforming Growth Factor beta, Transplantation, Homologous
  • Digital Object Identifier (doi)

    Author List

  • Asiedu C; Meng Y; Wang W; Huang Z; Contreras JL; George JF; Thomas JM
  • Start Page

  • 372
  • End Page

  • 380
  • Volume

  • 67
  • Issue

  • 3