title: Inhibition of interleukin-17 promotes differentiation of CD25⁻ cells into stable T regulatory cells in patients with autoimmune hepatitis.
abstract: OBJECTIVE
  Patients with autoimmune hepatitis (AIH) have reduced numbers and function of CD4+CD25(high)FOXP3+ T regulatory cells (Tregs). Tregs can be generated from CD25⁻ (ngTreg) cells, which suppress the immune response less efficiently than Tregs. We investigated whether their differentiation into T-helper (Th)17 cells, an effector subset that has the same CD4+ progenitors as Tregs, accounts for the reduced suppressive functions of ngTregs. We investigated whether blocking interleukin (IL)-17 increased the immunosuppressive activity of Tregs.
  
  
  METHODS
  ngTregs were generated from 36 patients with AIH and 23 healthy subjects (controls). During Treg differentiation, expression of IL-17 was inhibited by physical removal of IL-17-secreting cells, exposure to recombinant transforming growth factor β or neutralizing antibodies against IL-6 and IL-1β (to promote differentiation of ngTregs vs Th17 cells), small inhibitory RNAs specific for the Th17 transcription factor RORC, or a combination of all these approaches.
  
  
  RESULTS
  ngTregs from patients with AIH contained greater proportions of IL-17+ and RORC+ cells than Tregs from controls. All approaches to inhibit IL-17 increased expression of FOXP3 by ngTregs and their suppressive functions. Inhibition of IL-17 led to development of ngTregs that were phenotypically stable and did not acquire proinflammatory properties after exposure to IL-6 and IL-1β.
  
  
  CONCLUSIONS
  Blocking Th17 allows ngTregs to differentiate into functionally stable immune inhibitory cells; this approach might be developed for therapy of patients with AIH.
authors.affiliation: Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, London, England.
authors.forename: Maria Serena
authors.initials: MS
authors.lastname: Longhi
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Liberal
authors.forename: Beth
authors.initials: B
authors.lastname: Holder
authors.forename: Simon C
authors.initials: SC
authors.lastname: Robson
authors.forename: Yun
authors.initials: Y
authors.lastname: Ma
authors.forename: Giorgina
authors.initials: G
authors.lastname: Mieli-Vergani
authors.forename: Diego
authors.initials: D
authors.lastname: Vergani
mesh_terms: D000293:Adolescent; D000328:Adult; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D002648:Child; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D055785:Gene Knockdown Techniques; D019693:Hepatitis, Autoimmune / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053583:Interleukin-1beta / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis*; D015850:Interleukin-6 / Q000276:immunology; D008297:Male; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism; D013491:Suppressor Factors, Immunologic / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: D057134:Antibodies, Neutralizing; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D020381:Interleukin-17; D053583:Interleukin-1beta; D053645:Interleukin-2 Receptor alpha Subunit; D015850:Interleukin-6; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human; D013491:Suppressor Factors, Immunologic; D053773:Transforming Growth Factor beta1