title: A color-coded reporter model to study the effect of immunosuppressants on CD8+ T-cell memory in antitumor and alloimmune responses.
abstract: BACKGROUND
  Mammalian target of rapamycin (mTOR) inhibitors possess anticancer properties potentially useful in reducing posttransplantation malignancy. Besides controlling tumor-sensitive proliferative and angiogenic effects, mTOR influences transcription factors T-bet and Eomesodermin (Eomes) in CD8 cytotoxic T cells (Tc), which are key in rejecting tumors, and allografts.
  
  
  METHODS
  To study the role of mTOR in tumor and transplant immunity in an antigen-specific way, we used T-cell receptor transgenic B6.OTI recipients, B6.OVA.TG donors, and OVA-B16F10 melanoma cells. For tracking color-coded OTI-Tc cells associated with antitumor and alloimmunity in vivo, CD8-OTI transgenic reporter mice were created by crossbreeding DsRed-expressing B6.Nagy mice with B6.OTI mice.
  
  
  RESULTS
  The role of mTOR in regulating the differentiation and function of alloreactive Tc cells in vitro was explored by stimulating OTI-Tc cells with ovalbumin-transgenic antigen-presenting cells in the presence of rapamycin or tacrolimus. Rapamycin, but not tacrolimus, induced a pro-antitumor phenotypic shift from CD62LCD44 effector memory Tc cells to CD62LCD44 central memory Tc cells, which featured up-regulated levels of T-bet and Eomes and preserved levels of interferon-γ and perforin. For future investigations, an in vivo model was established whereby DsRedOTI-Tc cells adoptively transferred into B6 mice bearing either a ovalbumin-transgenic mouse skin transplant or OVA-B16F10 tumor could be traced by fluorescence-activated cell sorting analysis as effector or memory Tc cells in transplant and tumor tissues.
  
  
  CONCLUSIONS
  mTOR, but not calcineurin, inhibition spares antitumoral memory Tc cells by distinctively regulating T-bet and Eomes. This finding is now testable in a new tumor transplant model, which incorporates DsRedOTI-Tc cell tracing, opening the way to study the differential effects of immunosuppressants in posttransplantation malignancy.
authors.affiliation: Department of Surgery, University Hospital Regensburg, Regensburg, Germany.
authors.forename: Jordi
authors.initials: J
authors.lastname: Rovira
authors.forename: Manije
authors.initials: M
authors.lastname: Sabet-Baktach
authors.forename: Elke
authors.initials: E
authors.lastname: Eggenhofer
authors.forename: Margareta
authors.initials: M
authors.lastname: Lantow
authors.forename: Gudrun E
authors.initials: GE
authors.lastname: Koehl
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Schlitt
authors.forename: Josep M
authors.initials: JM
authors.lastname: Campistol
authors.forename: Edward K
authors.initials: EK
authors.lastname: Geissler
authors.forename: Alexander
authors.initials: A
authors.lastname: Kroemer
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D065095:Calcineurin Inhibitors; D007156:Immunologic Memory / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D018664:Interleukin-12 / Q000502:physiology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology*; D020123:Sirolimus / Q000494:pharmacology; D020825:T-Box Domain Proteins / Q000032:analysis; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D014184:Transplantation, Homologous / Q000276:immunology*; D000098815:T-bet Transcription Factor
chemical_list: D065095:Calcineurin Inhibitors; C491198:Eomes protein, mouse; D007166:Immunosuppressive Agents; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D018664:Interleukin-12; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus