title: Autoantigen-specific regulatory T cells, a potential tool for immune-tolerance reconstitution in type-2 autoimmune hepatitis.
abstract: Effector CD4 and CD8 T cell immune responses to cytochrome P450IID6 (CYP2D6), the autoantigen of autoimmune hepatitis type 2 (AIH-2), are permitted by a numerical and functional impairment of CD4(pos) CD25(high) regulatory T cells (T-regs). We aimed to investigate whether T-regs specific for CYP2D6 immunodominant regions and restricted by the appropriate human leukocyte antigen (HLA)-DR molecule can be generated in patients with AIH-2 and can control CD4 and CD8 T cell effectors targeting identical or overlapping CYP2D6 regions. CYP2D6-specific regulatory T cells (CYP2D6 T-regs) were obtained from peptide-pulsed monocyte-depleted peripheral blood mononuclear cells of 17 patients with AIH-2, who were positive for the predisposing HLA-DR7 and/or HLA-DR3 alleles. Their antigen specificity was assessed by cytofluorimetry using HLA class II tetramers and their cytokine profile by intracellular staining. T-reg ability to suppress was ascertained by measuring reduction of CD4(pos) CD25(neg) cell proliferation/effector cytokine secretion and of CD8 T cell cytotoxicity. The most efficient suppression of effector T cell proliferation, inflammatory cytokine release, and cytotoxicity was obtained by coculturing T-regs with CYP2D6-peptide-loaded semimature dendritic cells (smDCs), and smDC-CYP2D6 T-regs also expressed high levels of FOXP3 (forkhead box P3). Possession of the appropriate HLA-DR molecule and recognition of the CYP2D6 autoantigenic sequence were critical to the synergistic smDC-CYP2D6 T-reg immunoregulatory functions, and lack of either element led to poor control of responder cell proliferation and cytokine secretion. Moreover, interferon-γ neutralization significantly boosted the suppressive ability of CYP2D6 T-regs.
  
  
  CONCLUSIONS
  T-regs generated under CYP2D6-specific conditions and cocultured with smDCs are highly effective at controlling autoreactive T cells, thus providing the basis for a powerful and tailored form of immunotherapy for AIH-2.
authors.affiliation: Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, Denmark Hill, London, UK.
authors.forename: Maria Serena
authors.initials: MS
authors.lastname: Longhi
authors.forename: Munther J
authors.initials: MJ
authors.lastname: Hussain
authors.forename: William W
authors.initials: WW
authors.lastname: Kwok
authors.forename: Giorgina
authors.initials: G
authors.lastname: Mieli-Vergani
authors.forename: Yun
authors.initials: Y
authors.lastname: Ma
authors.forename: Diego
authors.initials: D
authors.lastname: Vergani
mesh_terms: D000293:Adolescent; D000328:Adult; D001323:Autoantibodies / Q000378:metabolism; D001324:Autoantigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D019389:Cytochrome P-450 CYP2D6 / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology / Q000502:physiology; D005260:Female; D015809:HLA-DR7 Antigen / Q000378:metabolism; D019693:Hepatitis, Autoimmune / Q000276:immunology* / Q000503:physiopathology / Q000628:therapy; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007167:Immunotherapy; D007223:Infant; D008297:Male; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology / Q000502:physiology; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D016207:Cytokines; D015809:HLA-DR7 Antigen; D019389:Cytochrome P-450 CYP2D6