CD4 T cell-dependent conditioning of dendritic cells to produce IL-12 results in CD8-mediated graft rejection and avoidance of tolerance

J Immunol. 2005 Jun 1;174(11):6909-17. doi: 10.4049/jimmunol.174.11.6909.

Abstract

Rejection of ectopic heart transplants expressing OVA requires OVA-specific CD4 and CD8 T cells. In the absence of CD4 T cells, OVA-specific CD8 T cells proliferate and migrate to the graft, but fail to develop cytolytic functions. With CD4 T cells present, clonal expansion of the CD8 T cells is only marginally increased but the cells now develop effector functions and mediate rapid graft rejection. In the presence of CD4 T cells, Ag and B7 levels do not increase on dendritic cells but IL-12 production is up-regulated, and this requires CD154 expression on the CD4 T cells. OVA-specific CD8 T cells lacking the IL-12 receptor fail to differentiate or mediate graft rejection even when CD4 T cells are present. Thus, CD4 T cells condition dendritic cells by inducing the production of IL-12, which is needed as the "third signal" for CD8 T cell differentiation and avoidance of tolerance.

MeSH terms

  • Actins / genetics
  • Animals
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / transplantation
  • CD40 Antigens / physiology
  • CD40 Ligand / biosynthesis
  • CD40 Ligand / physiology
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / transplantation
  • Cell Membrane / genetics
  • Cell Membrane / immunology
  • Cell Movement / genetics
  • Cell Movement / immunology
  • Cytotoxicity, Immunologic / genetics
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism*
  • Graft Rejection / genetics
  • Graft Rejection / immunology*
  • Heart Transplantation / immunology
  • Heart Transplantation / pathology
  • Interleukin-12 / biosynthesis*
  • Interleukin-12 / metabolism
  • Interleukin-12 / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Ovalbumin / genetics
  • Receptors, Interleukin / deficiency
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin-12
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Transplantation Conditioning* / methods
  • Transplantation Tolerance / genetics
  • Transplantation Tolerance / immunology*

Substances

  • Actins
  • CD40 Antigens
  • Receptors, Interleukin
  • Receptors, Interleukin-12
  • CD40 Ligand
  • Interleukin-12
  • Ovalbumin