Testicular Sertoli cells protect islet beta-cells from autoimmune destruction in NOD mice by a transforming growth factor-beta 1-dependent mechanism

Testicular Sertoli cells protect pancreatic islet grafts from allo- and aut oimmune destruction; however, the mechanism(s) of protection is unclear. Th e aim of this study was to determine whether Fas Ligand (FasL) and/or trans forming growth factor (TGF)-beta, immunoregulatory proteins produced by Ser toli cells, might mediate the protective effects of these cells against aut oimmune destruction of islet beta -cells, Sertoli cells were purified from testes of NOD mice and implanted under the right renal capsule of diabetic NOD mice, whereas NOD islets were implanted under the left renal capsule. O f the mice that received islet and Sertoli cells grafts, 64% (9 of 14) rema ined normoglycemic at 60 days posttransplantation compared with 0% (0 of 6) of the mice that received islet grafts alone, Immunohistochemical examinat ion of Sertoli cell, grafts in normoglycemic mice revealed that TGF-beta1 e xpression by Sertoli cells remained high, whereas FasL expression by Sertol i cells decreased progressively posttransplantation, Also, plasma levels of TGF-beta1 were significantly elevated in mice that received Sertoli cells and islet grafts, and anti-TGF-beta1 antibody administration completely abr ogated the protective effect of Sertoli cells on islet graft survival, wher eas anti-Fast antibody did not, Islet graft destruction in anti-TGF-beta1-t reated mice was associated with increases in interferon (IFN)-gamma -produc ing cells and decreases in interleukin (IL)-4-producing cells in the islet grafts. We conclude that 1) Sertoli cell production of TGF-beta1, not FasL, protects islet beta -cells from autoimmune destruction and 2) TGF-beta1 di verts islet-infiltrating cells from a beta -cell-destructive (IFN-gamma (+) ) phenotype to a nondestructive (IL-4(+)) phenotype.