title: The T helper 17-regulatory T cell axis in transplant rejection and tolerance.
abstract: OBJECTIVE
  Regulatory T cells (Tregs) are potential therapeutic tools in averting transplant rejection and promoting lifelong tolerance. However, Tregs can be subverted by inflammatory conditions, resulting in a T helper 17 (Th17) cell response. This review looks at the relationship between Tregs and Th17 cells.
  
  
  RESULTS
  Both naturally occurring and transforming growth factor-beta-induced Tregs can be converted into Th17 cells in the presence of inflammatory cytokines. Transforming growth factor-beta upregulates the Treg transcription factor, forkhead box P3, as well as the Th17 transcription factor, retinoic acid receptor-related orphan receptor gamma. However, forkhead box P3 binds to retinoic acid receptor-related orphan receptor gamma, inhibiting its promotion of IL-17 gene transcription. Inflammatory cytokines can disrupt this interaction through the inhibition of forkhead box P3 expression by signal transducer and activator of transcription 3.
  
  
  CONCLUSIONS
  The plasticity of the Treg population during inflammation presents a challenge to the use of Tregs as a therapeutic tool in solid organ transplantation. Investigations into the Th17-Treg axis have identified a number of potential pharmacological targets to avoid the risk of conversion to Th17 cells, but further work must be done before we can separate the benefits of Treg therapy from the hazards of the Th17 response.
authors.affiliation: Department of Nephrology and Transplantation, King's College London, Guy's Hospital, London, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Mitchell
authors.forename: Behdad
authors.initials: B
authors.lastname: Afzali
authors.forename: Giovanna
authors.initials: G
authors.lastname: Lombardi
authors.forename: Robert I
authors.initials: RI
authors.lastname: Lechler
mesh_terms: D000818:Animals; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D050835:Interferon Regulatory Factors; D020381:Interleukin-17 / Q000378:metabolism*; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D016377:Organ Transplantation / Q000009:adverse effects*; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D023001:Transplantation Tolerance; D014212:Tretinoin / Q000494:pharmacology; D000099218:Interferon Regulatory Factor-4
chemical_list: D051858:Forkhead Transcription Factors; D018836:Inflammation Mediators; D050835:Interferon Regulatory Factors; D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D016212:Transforming Growth Factor beta; D014212:Tretinoin; D000099218:Interferon Regulatory Factor-4; C539900:RORC protein, human