title: Regulatory T cells require mammalian target of rapamycin signaling to maintain both homeostasis and alloantigen-driven proliferation in lymphocyte-replete mice.
abstract: Rapamycin (Rapa), an immunosuppressive drug that acts through mammalian target of Rapa inhibition, broadly synergizes with tolerogenic agents in animal models of transplantation and autoimmunity. Rapa preferentially inhibits conventional CD4(+) Foxp3(-) T cells (Tconv) and promotes outgrowth of CD4(+)Foxp3(+) regulatory T cells (Treg) during in vitro expansion. Moreover, Rapa is widely perceived as augmenting both expansion and conversion of Treg in vivo. However, most quantitative studies were performed in lymphopenic hosts or in graft-versus-host disease models. We show in this study that in replete wild-type mice, Rapa significantly inhibits both homeostatic and alloantigen-induced proliferation of Treg, and promotes their apoptosis. Together, these lead to significant Treg depletion. Tconv undergo depletion to a similar degree, resulting in no change in the percent of Treg among CD4 cells. Moreover, in this setting, there was no evidence of conversion of Tconv into Treg. However, after withdrawal of Rapa, Treg recover Ag-induced proliferation more quickly than Tconv, leading to recovery to baseline numbers and an increase in the percent of Treg compared with Tconv. These findings suggest that the effects of Rapa on Treg survival, homeostasis, and induction, depend heavily on the cellular milieu and degree of activation. In vivo, the resistance of Treg to mammalian target of Rapa inhibition is relative and results from lymphopenic and graft-versus-host disease models cannot be directly extrapolated to settings more typical of solid organ transplantation or autoimmunity. Moreover, these results have important implications for the timing of Rapa therapy with tolerogenic agents designed to increase the number of Treg in vivo.
authors.affiliation: Thomas E Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Camirand
authors.forename: Yan
authors.initials: Y
authors.lastname: Lin
authors.forename: Monica
authors.initials: M
authors.lastname: Froicu
authors.forename: Songyan
authors.initials: S
authors.lastname: Deng
authors.forename: Warren D
authors.initials: WD
authors.lastname: Shlomchik
authors.forename: Fadi G
authors.initials: FG
authors.lastname: Lakkis
authors.forename: David M
authors.initials: DM
authors.lastname: Rothstein
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D055879:Gene Knock-In Techniques; D006706:Homeostasis / Q000187:drug effects / Q000276:immunology*; D007519:Isoantigens / Q000502:physiology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D018655:Lymphocyte Count; D008212:Lymphocyte Depletion; D008221:Lymphoid Tissue / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D020123:Sirolimus / Q000008:administration & dosage; D016038:Skin Transplantation / Q000276:immunology / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*
chemical_list: D007519:Isoantigens; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus