Constitutive OX40/OX40 ligand interaction induces autoimmune-like diseases

K Murata, M Nose, LC Ndhlovu, T Sato… - The Journal of …, 2002 - journals.aai.org
K Murata, M Nose, LC Ndhlovu, T Sato, K Sugamura, N Ishii
The Journal of Immunology, 2002journals.aai.org
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 …
Abstract
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.
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