A Novel Immunomodulatory Function for Semaphorin3F and Neuropilin-2 in Allograft Rejection.

Le résumé fourni par la source

The class3 semaphorins (Sema3A-G) bind to Neuropilin/Plexin complexes on tumor cells and elicit regulatory signals, anti-migration and anti-proliferation. Recently, we found that Sema3F modulates PI-3K-Akt and MAPK signaling via neuropilin-2 (NRP-2), suggesting that this ligand-receptor interaction may be potent to inhibit T cell activation responses. However, the role of Sema3F and NRP-2 in immunity is currently unexplored. In these studies, we initially treated C57BL/6 recipients of fully mismatched BALB/c cardiac allografts with Sema3F and find that it is potent to inhibit rejection; mean graft survival was 23.4 days (when administered via i.p. injection of Sema3F transfected cells on day 0,2,4 and 6, n=16 mice, P<0.0001) and 26.2 days (when administered IV via adenovirus on day -3, n=4 mice, P<0.005) vs. controls (mean survival 6.5 days, n=8). Addition of a blocking anti-Sema3F antibody to Sema3F-treated recipients (i.p. injection model) reduced graft survival to control (mean survival 7.5 days, n=4). By qPCR, FACS and Western blot, we find that the Sema3F receptor NRP-2 is expressed on T cell subsets at baseline, and its expression is markedly induced on CD4+ effectors and regulatory cells following 6hr anti-CD3-activation. By qPCR, CD4+ T cells were also found to express Plexin A1-4, further indicating that Sema3F may elicit its regulatory signaling via the NRP-2/Plexin complex. To determine function, we generated NRP-2-/- (ko) mice; in vitro, we find that CD4+ T cells derived from these mice are hyperproliferative (˜3 fold incr. vs. WT) and produce increased IL-2 and IFNγ (˜3 and ˜5 fold incr. vs. WT cells) in response to anti-CD3. Hyperactivation was most notable in NRP-2ko CD4+CD25- T cells vs. CD4+CD25+ subsets. Finally, NRP-2ko recipients of minor mismatched B6.C-H-2bm12 donor cardiac transplants were found to reject grafts at an accelerated rate (mean graft survival 32 days, n=5, P<0.005), vs. WT mice (mean graft survival >54 days, n=11). In addition, in preliminary studies, we find that Sema3F did not increase graft survival in NRP-2ko recipients of fully mismatched allografts vs. controls. Collectively, these findings for the first time define Sema3F as a novel immunomodulatory protein and suggest that Sema3F-NRP-2 interactions are of great importance in the regulation of allogeneic responses. DISCLOSURE:Briscoe, D.: Grant/Research Support, Pfizer.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.