test Browse by Author Names Browse by Titles of Works Browse by Subjects of Works Browse by Issue Dates of Works

Advanced Search
& Collections
Issue Date   
Sign on to:   
Receive email
My Account
authorized users
Edit Profile   
About T-Space   

T-Space at The University of Toronto Libraries >
School of Graduate Studies - Theses >
Doctoral >

Please use this identifier to cite or link to this item: http://hdl.handle.net/1807/17420

Title: The Immunoregulatory Role of FGL2 as a Novel Effector Molecule of Treg Cells
Authors: Shalev, Itay
Advisor: Levy, Gary A.
Department: Immunology
Keywords: Immunology
Treg cells
Issue Date: 18-Jun-2009
Abstract: Background and Aim: CD4+CD25+ regulatory T (Treg) cells are important in the maintenance of self-tolerance, regulation of T cell homeostasis, prevention of allograft rejection and in the modulation of immune responses to pathogens. Several groups have recently reported an increased expression of fgl2 in Treg cells by microarray analysis. FGL2, a member of the fibrinogen-like family, was previously shown to act as an immunomodulator by inhibiting DC maturation and T cell proliferation. Based on these findings, the immunoregulatory role of FGL2 as a novel effector molecule of Treg cells was investigated. Results: In agreement with previous studies, high levels of fgl2 transcripts were detected in Treg cells by real-time PCR. In fgl2-/- mice, an increased number and percentage of Treg cells were found with a greater expression of Foxp3 compared with fgl2+/+ Treg cells; however, the suppressive activity of fgl2-/- Treg cells was significantly impaired. Antibody to FGL2 completely inhibited the activity of fgl2+/+ Treg cells in vitro. Consistent with FGL2 contribution to Treg cell activity, targeted deletion of the gene led to an increased immune reactivity of DC, T cells and B cells, and the manifestation of glomerular autoimmunity in aged fgl2-/- mice. The importance of FGL2 as an effector of Treg cells was also demonstrated in MHV-3-induced fulminant hepatitis. Uninfected susceptible BALB/cJ mice had increased numbers of Treg cells and expression of FGL2 compared to uninfected resistant A/J mice. Following MHV-3 infection, plasma levels of FGL2 in BALB/cJ mice were significantly increased, correlating with an increased percentage of Treg cells. Treatment with anti-FGL2 antibody completely inhibited Treg cell activity and protected susceptible BALB/cJ mice against MHV-3-induced liver injury and mortality. Adoptive transfer of fgl2+/+ Treg cells into resistant fgl2-/- mice increased their mortality following MHV-3 infection. Finally, FGL2 treatment led to prolonged skin graft survival in a murine allotransplant model. The suppressive activity of FGL2 was mediated through binding to the inhibitory FcγRIIB receptor expressed on APCs, resulting in inhibition of DC maturation and induction of B cell apoptosis. Conclusion: These studies indicate that FGL2 plays an important immunoregulatory role as an effector cytokine of Treg cells; targeting FGL2 may provide a novel therapeutic approach for the treatment of patients with viral hepatitis, autoimmunity and transplant rejection.
URI: http://hdl.handle.net/1807/17420
Appears in Collections:Doctoral
Department of Immunology - Doctoral theses

Files in This Item:

File Description SizeFormat
Shalev_Itay_200906_PhD_thesis.pdf6.1 MBAdobe PDF

Items in T-Space are protected by copyright, with all rights reserved, unless otherwise indicated.