title: Thymic NF-κB-inducing kinase regulates CD4+T cell-elicited liver injury and fibrosis in mice.
abstract: The liver is an immunologically-privileged organ. Breakdown of liver immune privilege has been reported in chronic liver disease; however, the role of adaptive immunity in liver injury is poorly defined. Nuclear factor-κB-inducing kinase (NIK) is known to regulate immune tissue development, but its role in maintaining liver homeostasis remains unknown. This study aimed to assess the role of NIK, particularly thymic NIK, in regulating liver adaptive immunity.
  
  
  
  NIK was deleted systemically or conditionally using the Cre/loxp system. Cluster of differentiation [CD]4+or CD8+T cells were depleted using anti-CD4 or anti-CD8 antibody. Donor bone marrows or thymi were transferred into recipient mice. Immune cells were assessed by immunohistochemistry and flow cytometry.
  
  
  
  Global, but not liver-specific or hematopoietic lineage cell-specific, deletion of NIK induced fatal liver injury, inflammation, and fibrosis. Likewise, adoptive transfer of NIK-null, but not wild-type, thymi into immune-deficient mice induced liver inflammation, injury, and fibrosis in recipients. Liver inflammation was characterized by a massive expansion of T cells, particularly the CD4+T cell subpopulation. Depletion of CD4+, but not CD8+, T cells fully protected against liver injury, inflammation, and fibrosis in NIK-null mice. NIK deficiency also resulted in inflammation in the lung, kidney, and pancreas, but to a lesser degree relative to the liver.
  
  
  
  Thymic NIK suppresses development of autoreactive T cells against liver antigens, and NIK deficiency in the thymus results in CD4+T cell-orchestrated autoimmune hepatitis and liver fibrosis. Thus, thymic NIK is essential for the maintenance of liver immune privilege and liver homeostasis.
  
  
  
  We found that global or thymus-specific ablation of the NIK gene results in fatal autoimmune liver disease in mice. NIK-deficient mice develop liver inflammation, injury, and fibrosis. Our findings indicate that thymic NIK is essential for the maintenance of liver integrity and homeostasis.
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Sheng
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Yeung-Hyen
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, the Institute for Advanced Studies, Wuhan University, Wuhan 430072, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Kalyani
authors.initials: K
authors.lastname: Pyaram
authors.affiliation: Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Cheong-Hee
authors.initials: CH
authors.lastname: Chang
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: ruily@umich.edu.
authors.forename: Liangyou
authors.initials: L
authors.lastname: Rui
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019693:Hepatitis, Autoimmune / Q000209:etiology*; D008099:Liver / Q000276:immunology*; D008106:Liver Cirrhosis, Experimental / Q000209:etiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D013950:Thymus Gland / Q000502:physiology*; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D017346:Protein Serine-Threonine Kinases; D000097782:NF-kappaB-Inducing Kinase
keywords: CD4-positive T-lymphocytes; Flow Cytometry; Hepatitis, autoimmune; Inflammation; Liver cirrhosis; Liver disease; Liver fibrosis; Liver injury