title: mTOR Signaling Regulates Protective Activity of Transferred CD4+Foxp3+ T Cells in Repair of Acute Kidney Injury.
abstract: CD4+Foxp3+regulatory T cells (Tregs) are required for normal immune homeostasis. Recent studies suggested that Treg transfer facilitates recovery from acute kidney injury (AKI), but the molecular events that maintain Treg function after adoptive transfer remain unclear. This study aimed to investigate the regulation of mammalian target of rapamycin (mTOR) signaling in the Treg-mediated therapeutic effect on ischemic AKI. We noted significant Treg expansion in C57BL/6 mouse kidney, with enhanced immunosuppressive capacity after renal ischemia/reperfusion. mTOR inhibition significantly increased the frequency of Tregs in cultured CD4+T cells, with enhanced production of anti-inflammatory cytokines, which, conversely, was reduced by mTOR activation. Rapamycin, an inhibitor of mTOR, was transiently administered to C57BL/6 mice before ischemia/reperfusion surgery. No beneficial effect of rapamycin treatment was seen in the early recovery of AKI as a result of its inhibitory effect on tubular regeneration. However, rapamycin markedly enhanced the expansion of kidney Tregs, with increased mRNA expression of anti-inflammatory cytokines. Adoptive transfer of rapamycin-treated Tregs markedly suppressed conventional T cells, responder myeloid cells, and reactive myofibroblasts; however, it promoted host Tregs and alternative macrophages, leading to better renal function and less kidney fibrosis. Taken together, Treg transfer with mTOR inhibition markedly improves outcomes of ischemic AKI. These findings reveal an important role for mTOR signaling in maintaining Treg activity after adoptive transfer and highlight the therapeutic potential of targeting Tregs in acute and chronic kidney disease.
authors: Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China; chenguochun@hotmail.com chenhuihuiliko@gmail.com.
authors: Guochun
authors: G
authors: Chen
authors: Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China.|Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood Veterans Affairs Medical Center, Augusta, GA 30912; and.
authors: Zheng
authors: Z
authors: Dong
authors: Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China.
authors: Hong
authors: H
authors: Liu
authors: Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China.
authors: Yu
authors: Y
authors: Liu
authors: Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China.
authors: Shaobin
authors: S
authors: Duan
authors: Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China.
authors: Yinghong
authors: Y
authors: Liu
authors: Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China.
authors: Fuyou
authors: F
authors: Liu
authors: Department of Ophthalmology, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China chenguochun@hotmail.com chenhuihuiliko@gmail.com.
authors: Huihui
authors: H
authors: Chen
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy / Q000276:immunology* / Q000628:therapy*; D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D007511:Ischemia / Q000188:drug therapy / Q000276:immunology / Q000628:therapy; D007668:Kidney / Q000098:blood supply / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D012038:Regeneration; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus