title: Rapamycin generates graft-homing murine suppressor CD8(+) T cells that confer donor-specific graft protection.
abstract: It has been reported that rapamycin (RPM) can induce de novo conversion of the conventional CD4(+)Foxp3(-) T cells into CD4(+)Foxp3(+) regulatory T cells (iTregs) in transplantation setting. It is not clear whether RPM can similarly generate  suppressor CD8(+) T cells to facilitate graft acceptance. In this study, we investigated the ability of short-term RPM treatment in promoting long-term acceptance (LTA) of MHC-mismatched skin allografts by generating a CD8(+) suppressor T-cell population. We found that CD4  knockout (KO) mice (in C57BL/6 background, H-2(b)) can promptly reject DBA/2 (H-2(d)) skin allografts with mean survival time (MST) being 13 days (p < 0.01). However, a short course RPM treatment in these animals induced LTA with graft MST longer than 100 days.  Adoptive transfer of CD8(+) T cells from LTA group into recombination-activating gene 1 (Rag-1)-deficient mice provided donor-specific protection of DBA/2 skin grafts against cotransferred conventional CD8(+) T cells. Functionally active immunoregulatory CD8(+) T  cells also resided in donor skin allografts. Eighteen percent of CD8(+) suppressor T cells expressed CD28 as measured by flow cytometry, and produced reduced levels of IFN-γ, IL-2, and IL-10 in comparison to CD8(+) effector T cells as measured by ELISA. It is unlikely  that CD8(+) suppressor T cells mediated graft protection via IL-10, as IL-10/Fc fusion protein impaired RPM-induced LTA in CD4 KO mice. Our data supported the notion that RPM-induced suppressor CD8(+) T cells home to the allograft and exert donor-specific graft protection.
authors: Department of Medicine, Transplant Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors: Basset
authors: B
authors: El Essawy
authors: Prabhakar
authors: P
authors: Putheti
authors: Wenda
authors: W
authors: Gao
authors: Terry B
authors: TB
authors: Strom
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D006084:Graft Rejection / Q000401:mortality / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020123:Sirolimus / Q000494:pharmacology*; D012867:Skin / Q000473:pathology; D016038:Skin Transplantation; D014184:Transplantation, Homologous
chemical_list: D007166:Immunosuppressive Agents; D007376:Interleukin-2; D016753:Interleukin-10; D007371:Interferon-gamma; D020123:Sirolimus