Production of Proinflammatory Cytokines by Monocytes in Liver-Transplanted Recipients with De Novo Autoimmune Hepatitis Is Enhanced and Induces TH1-like Regulatory T Cells

被引:58
作者
Arterbery, Adam S. [1 ]
Osafo-Addo, Awo [1 ]
Avitzur, Yaron [2 ]
Ciarleglio, Maria [3 ]
Deng, Yanhong [4 ]
Lobritto, Steven J. [5 ]
Martinez, Mercedes [5 ]
Hafler, David A. [6 ]
Kleinewietfeld, Markus [7 ,8 ]
Ekong, Udeme D. [1 ]
机构
[1] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06520 USA
[2] Univ Toronto, Dept Pediat, Toronto, ON MSG 1X8, Canada
[3] Yale Univ, Sch Publ Hlth, Dept Biostat, New Haven, CT 06520 USA
[4] Yale Univ, Sch Publ Hlth, Yale Ctr Analyt Sci, New Haven, CT 06520 USA
[5] Columbia Univ, Dept Pediat, New York, NY 10032 USA
[6] Yale Univ, Sch Med, Dept Neurol & Immunobiol, New Haven, CT 06520 USA
[7] Tech Univ Dresden, Dept Clin Pathobiochem, Med Fac Carl Gustav Carus, D-01307 Dresden, Germany
[8] Hasselt Univ, VIB Lab Translat Immunomodulat, Biomed Res Inst, BE-3590 Diepenbeek, Belgium
基金
美国国家卫生研究院; 欧洲研究理事会;
关键词
ROR-GAMMA-T; IMMUNE HEPATITIS; FOLLOW-UP; ALLOGRAFT DYSFUNCTION; GRAFT FIBROSIS; RISK-FACTORS; DIFFERENTIATION; BLOOD; ANTIBODIES; ARTHRITIS;
D O I
10.4049/jimmunol.1502276
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
A subset of human regulatory T cells (Tregs) can secrete IFN-gamma or IL-17, and thus share features of T(H)1 or T(H)17 effector cells and lose suppressive function. The main factors driving this differentiation of Tregs toward a proinflammatory phenotype include IL-12 for T(H)1-like and IL-6 for T(H)17-type Tregs. In this study we show that Tregs of patients with de novo autoimmune hepatitis (dAIH) display increased frequencies of proinflammatory IFN-gamma and IL-17 cytokines. Irrespective of a fully demethylated FOXP3 locus, Tregs of subjects with dAIH are functionally impaired. In line with the observed Treg phenotype, we detected the presence of two dominant cytokines (IL-12 and IL-6) clustering with CD68(+) monocyte/macrophage cells in livers of subjects with dAIH, and isolated monocytes of subjects with dAIH secrete high levels of proinflammatory IL-12 and IL-6, suggesting that this inflammatory milieu is key for functional impairment of Tregs. Importantly, the blockade of IFN-gamma partially restores suppressive function of Tregs of subjects with dAIH, indicating that monocyte/macrophage-derived triggers might play a central role in Treg dysfunction and pathogenesis of dAIH.
引用
收藏
页码:4040 / 4051
页数:12
相关论文
共 55 条
[1]   Glutathione S-transferase T1 mismatch constitutes a risk factor for De Novo immune hepatitis after liver transplantation [J].
Aguilera, I ;
Sousa, JM ;
Gavilán, F ;
Bernardos, A ;
Wichmann, I ;
Nuñez-Roldán, A .
LIVER TRANSPLANTATION, 2004, 10 (09) :1166-1172
[2]   Antibodies against glutathione S-transferase T1 (GSTT1) in patients with de novo immune hepatitis following liver transplantation [J].
Aguilera, I ;
Wichmann, I ;
Sousa, JM ;
Bernardos, A ;
Franco, E ;
García-Lozano, JR ;
Núñez-Roldán, A .
CLINICAL AND EXPERIMENTAL IMMUNOLOGY, 2001, 126 (03) :535-539
[3]   Complement Component 4d Immunostaining in Liver Allografts of Patients With De Novo Immune Hepatitis [J].
Aguilera, Isabel ;
Manuel Sousa, Jose ;
Gavilan, Francisco ;
Gomez, Lourdes ;
Alvarez-Marquez, Antonia ;
Nunez-Roldan, Antonio .
LIVER TRANSPLANTATION, 2011, 17 (07) :779-788
[4]   Metabolic control of the Treg/Th17 axis [J].
Barbi, Joseph ;
Pardoll, Drew ;
Pan, Fan .
IMMUNOLOGICAL REVIEWS, 2013, 252 :52-77
[5]   DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3+ conventional T cells [J].
Baron, Udo ;
Floess, Stefan ;
Wieczorek, Georg ;
Baumann, Katrin ;
Gruetzkau, Andreas ;
Dong, Jun ;
Thiel, Andreas ;
Boeld, Tina J. ;
Hoffmann, Petra ;
Edinger, Matthias ;
Tuerbachova, Ivana ;
Hamann, Alf ;
Olek, Sven ;
Huehn, Jochen .
EUROPEAN JOURNAL OF IMMUNOLOGY, 2007, 37 (09) :2378-2389
[6]   IL-17-producing human peripheral regulatory T cells retain suppressive function [J].
Beriou, Gaelle ;
Costantino, Cristina M. ;
Ashley, Charles W. ;
Yang, Li ;
Kuchroo, Vijay K. ;
Baecher-Allan, Clare ;
Hafler, David A. .
BLOOD, 2009, 113 (18) :4240-4249
[7]   Expression of RORγt Marks a Pathogenic Regulatory T Cell Subset in Human Colon Cancer [J].
Blatner, Nichole R. ;
Mulcahy, Mary F. ;
Dennis, Kristen L. ;
Scholtens, Denise ;
Bentrem, David J. ;
Phillips, Joseph D. ;
Ham, Soo ;
Sandall, Barry P. ;
Khan, Mohammad W. ;
Mahvi, David M. ;
Halverson, Amy L. ;
Stryker, Steven J. ;
Boller, Anne-Marie ;
Singal, Ashima ;
Sneed, Rebekka K. ;
Sarraj, Bara ;
Ansari, Mohammed Javeed ;
Oft, Martin ;
Iwakura, Yoichiro ;
Zhou, Liang ;
Bonertz, Andreas ;
Beckhove, Philipp ;
Gounari, Fotini ;
Khazaie, Khashayarsha .
SCIENCE TRANSLATIONAL MEDICINE, 2012, 4 (164)
[8]   Monocytes from Patients with Type 1 Diabetes Spontaneously Secrete Proinflammatory Cytokines Inducing Th17 Cells [J].
Bradshaw, Elizabeth M. ;
Raddassi, Khadir ;
Elyaman, Wassim ;
Orban, Tihamer ;
Gottlieb, Peter A. ;
Kent, Sally C. ;
Hafler, David A. .
JOURNAL OF IMMUNOLOGY, 2009, 183 (07) :4432-4439
[9]   Long-Term Outcomes in Pediatric Liver Transplantation [J].
Bucuvalas, John .
LIVER TRANSPLANTATION, 2009, 15 (11) :S6-S11
[10]   Integrative analysis of RNA, translation, and protein levels reveals distinct regulatory variation across humans [J].
Cenik, Can ;
Cenik, Elif Sarinay ;
Byeon, Gun W. ;
Grubert, Fabian ;
Candille, Sophie I. ;
Spacek, Damek ;
Alsallakh, Bilal ;
Tilgner, Hagen ;
Araya, Carlos L. ;
Tang, Hua ;
Ricci, Emiliano ;
Snyder, Michael P. .
GENOME RESEARCH, 2015, 25 (11) :1610-1621