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Targeted Deletion of fgl2 Leads to Impaired Regulatory T Cell Activity and Development of Autoimmune Glomerulonephritis¹

Itay Shalev^2,*, Hao Liu^2,*, Cheryl Koscik^*, Agata Bartczak^*, Mojib Javadi^*, Kit Man Wong^*, Asif Maknojia^*, Wei He^*, Ming Feng Liu^*, Jun Diao^*, Erin Winter^*, Justin Manuel^*, Doug McCarthy, Mark Cattral^*,, Jennifer Gommerman, David A. Clark^*, M. James Phillips^*, Reginald R. Gorczynski^*,,, Li Zhang^*,,, Greg Downey^*,¶, David Grant^*,, Myron I. Cybulsky^*, and Gary Levy^3,*,,¶

^* Multi Organ Transplant Program, Department of Immunology, Department of Surgery, Department of Laboratory Medicine and Pathology, and ^¶ Department of Medicine, University of Toronto, Toronto, Ontario, Canada

Mice with targeted deletion of fibrinogen-like protein 2 (fgl2) spontaneously developed autoimmune glomerulonephritis with increasing age, as did wild-type recipients reconstituted with fgl2^–/– bone marrow. These data implicate FGL2 as an important immunoregulatory molecule and led us to identify the underlying mechanisms. Deficiency of FGL2, produced by CD4⁺CD25⁺ regulatory T cells (Treg), resulted in increased T cell proliferation to lectins and alloantigens, Th 1 polarization, and increased numbers of Ab-producing B cells following immunization with T-independent Ags. Dendritic cells were more abundant in fgl2^–/– mice and had increased expression of CD80 and MHCII following LPS stimulation. Treg cells were also more abundant in fgl2^–/– mice, but their suppressive activity was significantly impaired. Ab to FGL2 completely inhibited Treg cell activity in vitro. FGL2 inhibited dendritic cell maturation and induced apoptosis of B cells through binding to the low-affinity FcRIIB receptor. Collectively, these data suggest that FGL2 contributes to Treg cell activity and inhibits the development of autoimmune disease.

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 grants from the Heart and Stroke Foundation of Canada (T5686) and the Canadian Institutes for Health Research (GR13298, 79561, and STP 53882).

² I.S. and H.L. contributed equally to this study.

³ Address correspondence and reprint requests to Dr. Gary Levy, Toronto General Hospital, 585 University Avenue, Toronto, Ontario M5G 2C2, Canada. E-mail address: glfgl2{at}attglobal.net

⁴ Abbreviations used in this paper: DC, dendritic cell; Treg, regulatory T cell; PAS, periodic acid-Schiff; BM, bone marrow; MLR, mixed lymphocyte reaction; PI, propidium iodide; PALS, peri-arteriolar lymphoid sheath; GC, germinal center.

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The JI 2008 180: 1-2. [Full Text]