Transplantation survival is maintained by granzyme B+ regulatory cells and adaptive regulatory T cells

Granzyme B (GZB) has been implicated as an effector mechanism in regulatory T cells (T-reg) suppression. In a model of T-reg-dependent graft tolerance, it is shown that GZB- deficient mice are unable to establish long-term tolerance. Moreover, mice overexpressing the inhibitor of GZB, serine protease inhibitor 6, are also resistant to tolerization to alloantigen. Graft survival was shorter in bone marrow-mixed chimeras reconstituted with GZB-deficient T-reg as compared with wild-type T-reg. Whereas there was no difference in graft survival in mixed chimeras reconstituted with wild-type, perforin-deficient, or Fas ligand-deficient T-reg. Finally, data also show that if alloreactive effectors cannot express FoxP3 and be induced to convert in the presence of competent T-reg, then graft tolerance is lost. Our data are the first in vivo data to implicate GZB expression by T-reg in sustaining long-lived graft survival.