CD70 signaling is critical for CD28-independent CD8+ T cell-mediated alloimmune responses in vivo

J Immunol. 2005 Feb 1;174(3):1357-64. doi: 10.4049/jimmunol.174.3.1357.

Abstract

The inability to reproducibly induce robust and durable transplant tolerance using CD28-B7 pathway blockade is in part related to the persistence of alloreactive effector/memory CD8(+) T cells that are less dependent on this pathway for their cellular activation. We studied the role of the novel T cell costimulatory pathway, CD27-CD70, in alloimmunity in the presence and absence of CD28-B7 signaling. CD70 blockade prolonged survival of fully mismatched vascularized cardiac allografts in wild-type murine recipients, and in CD28-deficient mice induced long-term survival while significantly preventing the development of chronic allograft vasculopathy. CD70 blockade had little effect on CD4(+) T cell function but prevented CD8(+) T cell-mediated rejection, inhibited the proliferation and activation of effector CD8(+) T cells, and diminished the expansion of effector and memory CD8(+) T cells in vivo. Thus, the CD27-CD70 pathway is critical for CD28-independent effector/memory CD8(+) alloreactive T cell activation in vivo. These novel findings have important implications for the development of transplantation tolerance-inducing strategies in primates and humans, in which CD8(+) T cell depletion is currently mandatory.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acute Disease
  • Adoptive Transfer
  • Animals
  • Antibodies, Blocking / administration & dosage
  • Antibodies, Monoclonal / administration & dosage
  • Antigens, CD / immunology
  • Antigens, CD / physiology*
  • CD27 Ligand
  • CD28 Antigens / genetics
  • CD28 Antigens / physiology*
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / transplantation
  • CD8-Positive T-Lymphocytes / immunology*
  • Chronic Disease
  • Down-Regulation / immunology
  • Graft Rejection / genetics
  • Graft Rejection / immunology
  • Graft Survival / genetics
  • Graft Survival / immunology
  • Heart Transplantation / immunology*
  • Immunologic Memory / immunology
  • Isoantibodies / biosynthesis
  • Isoantibodies / blood
  • Killer Cells, Natural / immunology
  • Lymphocyte Activation / immunology
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / immunology
  • Membrane Proteins / physiology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Signal Transduction / immunology*
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Cytotoxic / metabolism
  • Th1 Cells / immunology
  • Th1 Cells / metabolism
  • Th2 Cells / immunology
  • Th2 Cells / metabolism
  • Transplantation, Heterotopic / immunology*
  • Tumor Necrosis Factor Receptor Superfamily, Member 7 / physiology
  • Up-Regulation / immunology

Substances

  • Antibodies, Blocking
  • Antibodies, Monoclonal
  • Antigens, CD
  • CD27 Ligand
  • CD28 Antigens
  • Cd70 protein, mouse
  • Isoantibodies
  • Membrane Proteins
  • Tumor Necrosis Factor Receptor Superfamily, Member 7