Constitutive OX40/OX40 ligand interaction induces autoimmune-like diseases.
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.
Murata
Kazuko
K
Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aobu-ku, Sendai 980-8575, Japan.
Nose
Masato
M
Ndhlovu
Lishomwa C
LC
Sato
Takayuki
T
Sugamura
Kazuo
K
Ishii
Naoto
N
D019264:Adoptive Transfer; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis / Q000097:blood; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000637:transplantation; D017637:Clonal Deletion / Q000235:genetics; D003433:Crosses, Genetic; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D007156:Immunologic Memory / Q000235:genetics; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D008024:Ligands; D008206:Lymphatic Diseases / Q000235:genetics / Q000276:immunology; D018655:Lymphocyte Count; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053278:OX40 Ligand; D009928:Organ Specificity / Q000235:genetics / Q000276:immunology; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; D013163:Splenomegaly / Q000235:genetics / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000502:physiology*; D048069:Tumor Necrosis Factors
D001323:Autoantibodies; D016207:Cytokines; D004268:DNA-Binding Proteins; D018984:Epitopes, T-Lymphocyte; D008024:Ligands; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; C499308:Rag2 protein, mouse; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; C505717:Tnfrsf4 protein, mouse; C504586:Tnfsf4 protein, mouse; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D048069:Tumor Necrosis Factors; C064655:V(D)J recombination activating protein 2