Constitutive OX40/OX40 ligand interaction induces autoimmune-like diseases

J Immunol. 2002 Oct 15;169(8):4628-36. doi: 10.4049/jimmunol.169.8.4628.


The interaction between OX40 and OX40 ligand (OX40L) is suggested to provide T cells with an effective costimulatory signals during T cell-APC interaction. To examine the in vivo effect of constitutive OX40/OX40L interaction during immune regulation, we report the establishment of OX40L-transgenic (OX40L-Tg) mice that constitutively express OX40L on T cells. Markedly elevated numbers of effector memory CD4(+) T cells, but not CD8(+) T cells, were observed in the secondary lymphoid organs of OX40L-Tg mice. Upon immunization with keyhole limpet hemocyanin in the absence of adjuvant, profound T cell proliferative responses and cytokine productions were seen in the OX40L-Tg mice as compared with wild-type mice. Furthermore, in OX40L-Tg mice administrated with superantigen, this constitutive OX40/OX40L interaction on CD4(+) T cells completely prevented normal in vivo clonal T cell deletion. Interestingly, OX40L-Tg mice on the C57BL/6 background spontaneously developed interstitial pneumonia and inflammatory bowel disease that was accompanied with a significant production of anti-DNA Ab in the sera. Surprisingly, these diseases were not evident on the OX40L-Tg mice on the BALB/c strain. However, such inflammatory diseases were successfully reproducible in recombination-activating gene (RAG)2-deficient mice upon transfer of OX40L-Tg CD4(+) T cells. Blockade of OX40/OX40L interaction in the recipient RAG2-deficient mice completely prevented disease development. The present results orchestrated in this study indicate that OX40/OX40L interaction may be a vital link in our understanding of T cell-mediated organ-specific autoimmunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Autoantibodies / biosynthesis
  • Autoantibodies / blood
  • Autoimmune Diseases / genetics
  • Autoimmune Diseases / immunology*
  • Autoimmune Diseases / pathology
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / pathology
  • CD4-Positive T-Lymphocytes / transplantation
  • Clonal Deletion / genetics
  • Crosses, Genetic
  • Cytokines / biosynthesis
  • Cytokines / blood
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • Epitopes, T-Lymphocyte / genetics
  • Epitopes, T-Lymphocyte / immunology
  • Immunologic Memory / genetics
  • Inflammation / genetics
  • Inflammation / immunology
  • Ligands
  • Lymphatic Diseases / genetics
  • Lymphatic Diseases / immunology
  • Lymphocyte Count
  • Membrane Glycoproteins / deficiency
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / physiology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Mice, Knockout
  • Mice, Transgenic
  • OX40 Ligand
  • Organ Specificity / genetics
  • Organ Specificity / immunology
  • Receptors, OX40
  • Receptors, Tumor Necrosis Factor*
  • Splenomegaly / genetics
  • Splenomegaly / immunology
  • Th2 Cells / immunology
  • Th2 Cells / metabolism
  • Tumor Necrosis Factor Receptor Superfamily, Member 7 / physiology*
  • Tumor Necrosis Factors


  • Autoantibodies
  • Cytokines
  • DNA-Binding Proteins
  • Epitopes, T-Lymphocyte
  • Ligands
  • Membrane Glycoproteins
  • OX40 Ligand
  • Rag2 protein, mouse
  • Receptors, OX40
  • Receptors, Tumor Necrosis Factor
  • Tnfrsf4 protein, mouse
  • Tnfsf4 protein, mouse
  • Tumor Necrosis Factor Receptor Superfamily, Member 7
  • Tumor Necrosis Factors
  • V(D)J recombination activating protein 2