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K.–H. Sonoda, T. Nakamura, P. Carmeliets, J. Stein–Streilein; NKT Cell–Derived Urokinase–Type Plasminogen Activator Promote Systemic Tolerance Associated With Eye . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1777.
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© ARVO (1962-2015); The Authors (2016-present)
In a model of systemic tolerance called, "Anterior Chamber Associated Immune Deviation" or ACAID, the differentiation of the T regulatory (Tr) cells depends on Natural Killer T (NKT) cells and occurs in the spleen. While it is known that thrombospondin contributes to activation of TGFb within the eye it is not clear how TGFb becomes activated in the spleen. We investigated the role of urokinase–type plasminogen activator (uPA) during the induction ACAID.
The RT–PCR and in vitro plasmin assay were performed to confirm the uPA production and biological activity, respectively. Splenic NKT cells were enriched by magnetic beads. ACAID regulatory T cells were detected by local adoptive transfer (LAT) assay. In brief: mice were inoculated (anterior chamber, a.c.) with ovalbumin (OVA) seven days prior to collecting enriched splenic T cells as regulatory cells. Regulatory cells were then mixed with OVA–primed T cells (effector) and OVA–pulsed APCs (stimulator), and co–transferred into the ear pinnae of naive C57BL/6 mice. Delayed type hypersensitivity responses were indicated by an increase in ear thickness 24 h later.
The RT–PCR and in vitro plasmin assay revealed that splenic invariant (i)NKT cells actually produced uPA and converted plasminogen to plasmin. We also found uPA knockout (KO) mice could not generate ACAID, even though they could recruit iNKT cells to the spleen and those NKT cells produced IL–10 after the inoculation of antigen into the anterior chamber. Although the adoptive transfer of splenic NKT cells from wild–type mice can restore ACAID in Ja18 KO mice (iNKT KO mice), NKT cells from uPA KO mice could not reconstitute ACAID in Ja18 KO mice.
uPA derived from CD1d–reactive invariant NKT cells is required for the induction of peripheral tolerance associated with eye. iNKT cell derived uPA presumably is responsible for the efficient enzymatic activation of latent TGFb in the periphery during ACAID induction.
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