Fibrinogen-like protein 1 induces LAG3 signaling to prevent costimulatory blockade resistant rejection 3500

Description CTLA4-Ig has shown significant promise in transplantation with improved long-term outcomes. However, CTLA4-Ig has not been widely adopted, due to the increased incidence of acute rejection mediated by memory T cells. A drawback of CTLA4-Ig is that it deprives Tregs of CTLA4 signaling, diminishing their suppressive capacity. The goal of this study was to test the potential of coinhibitory receptors in controlling costimulatory blockade resistant rejection. Lymphocyte Activation Gene 3 (LAG3), is a coinhibitory receptor expressed by many immune cells including Tregs and activated T cells and can be stimulated via its ligand Fibrinogen-like protein 1 (FGL1). In our murine heart transplant models treatment with CTLA4-Ig alone resulted in 100% of grafts rejected by day 16 (MST = 14d). Combined treatment of CTLA4-Ig with FGL1 prolonged allograft survival (MST = 28d), in a LAG3 dependent manner. At d10 posttransplant, recipient FGL1 treatment resulted in decreased frequencies of IFNγ+ graft infiltrating CD8 T cells. and increased levels of serum donor specific IgG at day 10, but with reduced complement deposition. Furthermore, FGL1-induced prolonged survival was dependent on Treg expression of LAG3 as combination FOXP3CreLAG3fl/fl recipients rejected their heart allografts by day 15 (MST = 11d) . These findings demonstrate that targeting coinhibitory receptors such as LAG3 may be attractive therapeutic targets for the prevention of costimulatory blockade resistant rejection. Funding Sources Supported by the Cleveland Clinic Global Center for Pathogen & Human Health Young Investigator Award Topic Categories Transplantation Immunology (TRAN)