Critical involvement of OX40 ligand signals in the T cell priming events during experimental autoimmune encephalomyelitis.
OX40 ligand (OX40L) expressed on APCs, and its receptor, OX40 present on activated T cells, are members of the TNF/TNFR family, respectively, and have been located at the sites of inflammatory conditions. We have observed in OX40L-deficient mice (OX40L(-/-)) an impaired APC capacity and in our recently constructed transgenic mice expressing OX40L (OX40L-Tg), a markedly enhanced T cell response to protein Ags. Using these mice, we demonstrate here the critical involvement of the OX40L-OX40 interaction during the T cell priming events in the occurrence of experimental autoimmune encephalomyelitis (EAE). In OX40L(-/-) mice, abortive T cell priming greatly reduced the clinical manifestations of actively induced EAE, coupled with a reduction in IFN-gamma, IL-2, and IL-6 production in vitro. Adoptive transfer experiments however revealed an efficient transfer of disease to OX40L(-/-) mice using wild-type donor T cells, indicating an intact capacity of OX40L(-/-) mice to initiate effector responses. On the other hand, OX40L(-/-) donor T cells failed to transfer disease to wild-type recipient mice. Furthermore, OX40L-Tg mice developed a greater severity of EAE despite a delayed onset, while both OX40L-Tg/CD28(-/-) and OX40L-Tg/CD40(-/-) mice failed to develop EAE demonstrating a requisite for these molecules. These findings indicate a pivotal role played by OX40L in the pathogenesis of EAE.
Ndhlovu
L C
LC
Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Ishii
N
N
Murata
K
K
Sato
T
T
Sugamura
K
K
D019264:Adoptive Transfer; D000818:Animals; D000941:Antigens / Q000008:administration & dosage; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008024:Ligands; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D053278:OX40 Ligand; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000276:immunology; D048069:Tumor Necrosis Factors
D000941:Antigens; D018106:CD28 Antigens; D007376:Interleukin-2; D015850:Interleukin-6; D008024:Ligands; D008562:Membrane Glycoproteins; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D053278:OX40 Ligand; 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; D007371:Interferon-gamma