Inhibition of Interleukin-17 Promotes Differentiation of CD25– Cells Into Stable T Regulatory Cells in Patients With Autoimmune Hepatitis

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 142; no. 7; pp. 1526 - 1535.e6
• Main Authors: Longhi, Maria Serena, Liberal, Rodrigo, Holder, Beth, Robson, Simon C., Ma, Yun, Mieli–Vergani, Giorgina, Vergani, Diego
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2012
• Subjects: Adolescent; Adult; Antibodies, Neutralizing - pharmacology; Cell Differentiation - immunology; Cell Proliferation; Child; Female; Forkhead Transcription Factors - metabolism; Gastroenterology and Hepatology; Gene Knockdown Techniques; Hepatitis, Autoimmune - immunology; Hepatitis, Autoimmune - metabolism; Humans; Immune Regulation; Immunophenotyping; Immunotherapy; Interleukin-17 - antagonists & inhibitors; Interleukin-17 - metabolism; Interleukin-1beta - immunology; Interleukin-2 Receptor alpha Subunit - analysis; Interleukin-6 - immunology; Liver Inflammation; Male; Nuclear Receptor Subfamily 1, Group F, Member 3 - metabolism; Suppressor Factors, Immunologic - metabolism; T-Cell Development; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Th17 Cells - immunology; Transforming Growth Factor beta1 - pharmacology; AIH; IL; SMA; Treg; siRNA; HS; PBMC; rTGF-β; IFN; T-Cell Development; MFI; ngTreg; rIL-2; TGF; ANA; Th; Immunotherapy; Immune Regulation; Liver Inflammation; anti–smooth muscle antibody; newly generated T regulatory cell; anti-nuclear antibody; healthy subjects; small interfering RNA; T-helper; autoimmune hepatitis; recombinant interleukin-2; interleukin; mean fluorescence intensity; T regulatory cell; recombinant transforming growth factor β; interferon; transforming growth factor; peripheral blood mononuclear cell
• ISSN: 0016-5085; 1528-0012; 1528-0012
• DOI: 10.1053/j.gastro.2012.02.041

Patients with autoimmune hepatitis (AIH) have reduced numbers and function of CD4+CD25highFOXP3+ 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. 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. 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. Blocking Th17 allows ngTregs to differentiate into functionally stable immune inhibitory cells; this approach might be developed for therapy of patients with AIH.