Critical, but conditional, role of OX40 in memory T cell-mediated rejection

J Immunol. 2006 Feb 1;176(3):1394-401. doi: 10.4049/jimmunol.176.3.1394.

Abstract

Memory T cells can be a significant barrier to the induction of transplant tolerance. However, the molecular pathways that can regulate memory T cell-mediated rejection are poorly defined. In the present study we tested the hypothesis that the novel alternative costimulatory molecules (i.e., ICOS, 4-1BB, OX40, or CD30) may play a critical role in memory T cell activation and memory T cell-mediated rejection. We found that memory T cells, generated by either homeostatic proliferation or donor Ag priming, induced prompt skin allograft rejection regardless of CD28/CD154 blockade. Phenotypic analysis showed that, in contrast to naive T cells, such memory T cells expressed high levels of OX40, 4-1BB, and ICOS on the cell surface. In a skin transplant model in which rejection was mediated by memory T cells, blocking the OX40/OX40 ligand pathway alone did not prolong the skin allograft survival, but blocking OX40 costimulation in combination with CD28/CD154 blockade induced long-term skin allograft survival, and 40% of the recipients accepted their skin allograft for >100 days. In contrast, blocking the ICOS/ICOS ligand and the 4-1BB/4-1BBL pathways alone or combined with CD28/CD154 blockade had no effect in preventing skin allograft rejection. OX40 blockade did not affect the homeostatic proliferation of T cells in vivo, but markedly inhibited the effector functions of memory T cells. Our data demonstrate that memory T cells resisting to CD28/CD154 blockade in transplant rejection are sensitive to OX40 blockade and suggest that OX40 is a key therapeutic target in memory T cell-mediated rejection.

MeSH terms

  • 4-1BB Ligand
  • Animals
  • Antigens, Differentiation, T-Lymphocyte / metabolism
  • CD28 Antigens / immunology
  • CD40 Ligand / immunology
  • Cell Proliferation
  • Cell Survival / immunology
  • Cells, Cultured
  • Epitopes / immunology
  • Graft Rejection / immunology*
  • Homeodomain Proteins / genetics
  • Immunologic Memory*
  • Inducible T-Cell Co-Stimulator Protein
  • Isoantigens / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Mice, Knockout
  • Receptors, OX40
  • Receptors, Tumor Necrosis Factor / metabolism
  • Receptors, Tumor Necrosis Factor / physiology*
  • Skin Transplantation / immunology
  • T-Lymphocytes / immunology*
  • Tumor Necrosis Factors / metabolism

Substances

  • 4-1BB Ligand
  • Antigens, Differentiation, T-Lymphocyte
  • CD28 Antigens
  • Epitopes
  • Homeodomain Proteins
  • Icos protein, mouse
  • Inducible T-Cell Co-Stimulator Protein
  • Isoantigens
  • Receptors, OX40
  • Receptors, Tumor Necrosis Factor
  • Tnfrsf4 protein, mouse
  • Tnfsf9 protein, mouse
  • Tumor Necrosis Factors
  • RAG-1 protein
  • CD40 Ligand