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Transplantation Survival Is Maintained by Granzyme B⁺ Regulatory Cells and Adaptive Regulatory T Cells

Department of Microbiology and Immunology, Dartmouth Medical School and Norris Cotton Cancer Center, Lebanon, NH 03756

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.

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¹ Address correspondence and reprint requests to Dr. Randolph Noelle, Department of Microbiology and Immunology, Dartmouth Medical School and Norris Cotton Cancer Center, Lebanon, NH 03756. E-mail address: rjn{at}dartmouth.edu

D.G. designed research, performed research, analyzed data, and wrote article V.D. performed research and reviewed the manuscript; E.N. performed research and reviewed the manuscript; L.-f.L. contributed vital tools and reviewed the manuscript; K.B. performed research and reviewed the manuscript; Z.S. contributed vital tools and reviewed the manuscript; and R.N. designed research and reviewed the manuscript.

² Abbreviations used in this paper: DST, donor-specific transfusion; AICD, activation-induced cell death; T^eff, effector t cell; T^reg, regulatory T cell; nT^reg, natural T^reg; aT^reg, adaptive T^reg; GZB, granzyme B; Spi-6, serine protease inhibitor 6; Wt, wild type; Tg, transgenic; LN, lymph node; Sf, scurfin; FasL, Fas ligand.