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* Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114;
Department of Ophthalmology, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan;
Laboratory of Experimental Immunology, National Cancer Institute-Frederick, Frederick, MD 21702;
Department of Microbiology and Infectious Disease, University of Calgary, Calgary, Alberta, Canada; and
¶ Center for Transgene Technology and Gene Therapy, Katholieke Universiteit Leuven, Leuven, Belgium
In a model of peripheral tolerance called anterior chamber-associated immune deviation (ACAID), the differentiation of the T regulatory cells depends on NKT cells and occurs in the spleen. In this study, we show that NKT cells that express the invariant (i) TCR and are the CD1d-reactive NKT cells (required for development of peripheral tolerance) actually produced urokinase-type plasminogen activator (uPA) during tolerance induction. The RT-PCR and in vitro plasmin assay showed that splenic iNKT cells derived uPA-converted plasminogen to plasmin. Moreover, uPA was required for tolerance induction because uPA knockout (KO) mice did not develop peripheral tolerance or develop CD8+ T regulatory cells after Ag inoculation into the anterior chamber. In contrast, other aspects of ACAID-induced tolerance, including recruitment of iNKT cells to the spleen and production of IL-10 by iNKT cells, were unchanged in uPA-deficient mice. The adoptive transfer of splenic NKT cells from wild-type mice restored ACAID in J
18 KO mice (iNKT cell deficient), but NKT cells from uPA KO mice did not. We postulate that the mechanism of action of uPA is through its binding to the uPAR receptor, and enzymatic cleavage of plasminogen to plasmin, which in turn activates latent TGF
. In conclusion, uPA derived from iNKT cells is required to induce peripheral tolerance via the eye.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by National Institutes of Health Public Health Service Grants R01 EY11983 and EY 13306.
2 Address correspondence and reprint requests to Dr. Joan Stein-Streilein, Schepens Eye Research Institute, 20 Staniford Street, Boston, MA 02114. E-mail address: joan.stein{at}schepens.harvard.edu
3 Abbreviations used in this paper: ACAID, anterior chamber-associated immune deviation; DH, delayed hypersensitivity; a.c., anterior chamber; Treg, T regulatory; KO, knockout; i, invariant; PA, plasminogen activator; tPA, tissue-type plasminogen activator; uPA, urokinase-type plasminogen activator; PEC, peritoneal exudate cell; WT, wild type; LAT, local adoptive transfer.
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