title: Rapamycin, and not cyclosporin A, preserves the highly suppressive CD27+ subset of human CD4+CD25+ regulatory T cells.
abstract: The immunosuppressive drugs rapamycin and cyclosporin A (CsA) are widely used to prevent allograft rejection. Moreover, they were shown to be instrumental in experimental models of tolerance induction. However, it remains to be elucidated whether these drugs have an effect on the CD4+ CD25+ regulatory T-cell (T(REG)) population, which plays an important role in allograft tolerance. Recently, we reported that alloantigen-driven expansion of human CD4+ CD25+ T(REG)s gives rise to a distinct highly suppressive CD27+ T(REG) subset next to a moderately suppressive CD27- T(REG) subset. In the current study we found that rapamycin and CsA do not interfere with the suppressive activity of human naturally occurring CD4+ CD25+ T cells. However, in contrast to CsA, rapamycin preserved the dominance of the potent CD27+ T(REG) subset over the CD27- T(REG) subset after alloantigen-driven expansion of CD4+ CD25+ T(REG)s in vitro. Accordingly, CD4+ CD25+ T(REG)s cultured in the presence of rapamycin displayed much stronger suppressive capacity than CD4+ CD25+ T(REG)s cultured in the presence of CsA. In addition, CD4+ CD25+ T(REG) cells cultured in the presence of rapamycin, but not CsA, were able to suppress ongoing alloimmune responses. This differential effect of rapamycin and CsA on the CD27+ T(REG) subset dominance may favor the use of rapamycin in tolerance-inducing strategies.
authors.affiliation: Department of Bloodtransfusion and Transplantation Immunology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Jeroen J A
authors.initials: JJ
authors.lastname: Coenen
authors.forename: Hans J P M
authors.initials: HJ
authors.lastname: Koenen
authors.forename: Esther
authors.initials: E
authors.lastname: van Rijssen
authors.forename: Luuk B
authors.initials: LB
authors.lastname: Hilbrands
authors.forename: Irma
authors.initials: I
authors.lastname: Joosten
mesh_terms: D002478:Cells, Cultured; D016572:Cyclosporine / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D006084:Graft Rejection / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects* / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007519:Isoantigens / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D020123:Sirolimus / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory; D014184:Transplantation, Homologous; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7
chemical_list: D007166:Immunosuppressive Agents; D007519:Isoantigens; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D016572:Cyclosporine; D020123:Sirolimus