title: Differential impact of mammalian target of rapamycin inhibition on CD4+CD25+Foxp3+ regulatory T cells compared with conventional CD4+ T cells.
abstract: Based on their ability to control T-cell homeostasis, Foxp3(+)CD4(+)CD25(+) regulatory T cells (Tregs) are being considered for treatment of autoimmune disorders and acute graft-versus-host disease (aGVHD). When combining Tregs with the immunosuppressant rapamycin (RAPA), we observed reduced alloreactive conventional T-cell (Tconv) expansion and aGVHD lethality compared with each treatment alone. This synergistic in vivo protection was paralleled by intact expansion of polyclonal Tregs with conserved high FoxP3 expression. In contrast to Tconv, activation of Tregs with alloantigen and interleukin-2 preferentially led to signal transducer and activator of transcription 5 (STAT5) phosphorylation and not phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway activity. Expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a negative regulator of the PI3K/Akt/mTOR pathway, remained high in Tregs but not Tconv during stimulation. Conversely, targeted deletion of PTEN increased susceptibility of Tregs to mTOR inhibition by RAPA. Differential impact of RAPA as a result of reduced usage of the mTOR pathway in Tregs compared with conventional T cells explains the synergistic effect of RAPA and Tregs in aGVHD protection, which has important implications for clinical trials using Tregs.
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Zeiser
authors.forename: Dennis B
authors.initials: DB
authors.lastname: Leveson-Gower
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Zambricki
authors.forename: Neeraja
authors.initials: N
authors.lastname: Kambham
authors.forename: Andreas
authors.initials: A
authors.lastname: Beilhack
authors.forename: John
authors.initials: J
authors.lastname: Loh
authors.forename: Jing-Zhou
authors.initials: JZ
authors.lastname: Hou
authors.forename: Robert S
authors.initials: RS
authors.lastname: Negrin
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects*; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases
chemical_list: D051858:Forkhead Transcription Factors; D007166:Immunosuppressive Agents; D053645:Interleukin-2 Receptor alpha Subunit; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D050799:STAT5 Transcription Factor; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C498833:Foxp3 protein, mouse; C546843:mTOR protein, mouse; C487757:Pten protein, mouse