P28 Defective T-regulatory function in autoimmune hepatitis may partially derive from a pro-inflammatory skewing of Gal9+T-regs. (6th September 2011)

• Record Type: Journal Article
• Authors: Liberal, R; Mieli-Vergani, G; Vergani, D; Longhi, M S
• Is Part Of: Gut. Volume 60:(2011)Supplement 2
• Page Start: A13
• Page End: A13
• Publication Date: 2011-09-06
• Subjects: Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2011-300857a.28
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Introduction: In autoimmune hepatitis (AIH) CD4 + CD25 + regulatory T-cells (T-regs) are defective in their ability to control CD4 T-cell effector function. T-regs express Galectin9 (Gal9), a β-galactosidase-binding-protein that inhibits Th1-mediated immune-responses by binding the T-cell-immunoglobulin-and-mucin-domain3 (Tim-3) on CD4 effector cells. In AIH T-regs express reduced levels of Gal9. Aim: To characterise lineage-specific transcription factor and cytokine profiles of peripheral-blood-derived Gal9 + T-regs in AIH. Method: 34 ANA/SMA+ patients (24 females; median age: 14.6 years) and 17 healthy subjects (HS, 12 females, median age: 29 years) were studied. The phenotype of circulating T-regs was determined by cytofluorimetry using CD4, CD25 and CD127 monoclonal antibodies. The frequency of cells positive for Gal9, FOXP3, T-bet, GATA3 and RORC and that of cells producing IFNγ, IL-10, TGF-β and IL-17 were determined by intracellular staining. T-reg suppressor function was evaluated in a proliferation assay following co-culture with CD25 - Tim-3 + and CD25 - Tim-3 − autologous target cells. Results: Within Gal9 + cells the frequency of: (1) FOXP3 + cells was lower in AIH than in HS (14.4±2 vs 42.8±3.1, p<0.001); (2) T-bet +, GATA3 + and RORC + cells was similar in AIH and HS; (3) IL-10-producing cells was lower in AIH than in HS (5.1±0.6 vs 9.1±0.5, p<0.001) but higher than in the Gal9 − T-reg fraction for both (AIH: 5.1±0.6 vs 2.3±0.2, p=0.001; HS: 9.1±0.5 vs 3.3±0.4, p<0.001); (4) TGF-β-producing cells was lower in AIH than in HS (6.4±0.7 vs 8.1±0.4, p=0.04); (5) IFNγ- and IL-17-producing cells was higher in AIH than in HS (IFNγ: 4.4±0.6 vs 2.1±0.3, p=0.002; IL-17: 4.1±0.6 vs 1.8±0.2, p=0.002). Treatment with anti-IL-10 neutralising antibodies reduced T-reg ability to suppress CD25 - Tim-3 + cell proliferation (AIH: 42% inhibition in the absence of antibodies vs 36% in their presence, p=0.06; HS: 56% vs 48%, p=0.04), while did not affect CD25 − Tim-3 − cell proliferation. Conclusion: A skewing towards a pro-inflammatory phenotype and a reduced proportion of FOXP3 + and IL-10-producing cells within Gal9 + T-regs may contribute to defective immunoregulation in AIH. The reduction of Gal9 + T-reg suppression following anti-IL-10 blockade both in health and AIH, suggests a role for IL-10 in Gal9 + T-cell immune-regulatory function.