Fibrinogen-like protein 2 (FGL2) is an immunomodulatory protein that is expressed by regulatory T cells (Tregs). The objective of this study was to determine if recombinant FGL2 (rFGL2) treatment or constitutive FGL2 overexpression could promote transplant tolerance in mice. Although rFGL2 treatment prevented rejection of fully mismatched cardiac allografts, all grafts were rejected after stopping treatment. Next, we generated FGL2 transgenic mice (fgl2 Tg ) that ubiquitously overexpressed FGL2. These mice developed normally and had no evidence of the autoimmune glomerulonephritis seen in fgl2 −/− mice. Immune characterization showed fgl2 Tg T cells were hypoproliferative to stimulation with alloantigens or anti-CD3 and anti-CD28 stimulation, and fgl2 Tg Tregs had increased immunosuppressive activity compared with fgl2 +/+ Tregs. To determine if FGL2 overexpression can promote tolerance, we transplanted fully mismatched cardiac allografts into fgl2 Tg recipients. Fifty percent of cardiac grafts were accepted indefinitely in fgl2 Tg recipients without any immunosuppression. Tolerant fgl2 Tg grafts had increased numbers and proportions of Tregs and tolerant fgl2 Tg mice had reduced proliferation to donor but not third party antigens. These data show that tolerance in fgl2 Tg recipients involves changes in Treg and T cell activity that contribute to a higher intragraft Treg–to–T cell ratio and acceptance of fully mismatched allografts.
Bibliographical noteFunding Information:
This work was supported by the Heart and Stroke Foundation (Ontario, Canada) and the Canadian Institutes of Health Research (CIHR). A.C. is supported by a postdoctoral award from the Heart and Stroke Foundation and CIHR Training Program in Regenerative Medicine. A.B. was funded by the Training Program in Regenerative Medicine and the Ontario Graduate Scholarship in Science and Technology.
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