title: Interleukin 17-producing γδT cells promote hepatic regeneration in mice.
abstract: OBJECTIVE
  Subsets of leukocytes synergize with regenerative growth factors to promote hepatic regeneration. γδT cells are early responders to inflammation-induced injury in a number of contexts. We investigated the role of γδT cells in hepatic regeneration using mice with disruptions in Tcrd (encodes the T-cell receptor δ chain) and Clec7a (encodes C-type lectin domain family 7 member a, also known as DECTIN1).
  
  
  METHODS
  We performed partial hepatectomies on wild-type C57BL/6, CD45.1, Tcrd(-/-), or Clec7a(-/-) mice. Cells were isolated from livers of patients and mice via mechanical and enzymatic digestion. γδT cells were purified by fluorescence-activated cell sorting.
  
  
  RESULTS
  In mice, partial hepatectomy up-regulated expression of CCL20 and ligands of Dectin-1, which was associated with recruitment and activation of γδT cells and their increased production of interleukin (IL)-17 family cytokines. Recruited γδT cells induced production of IL-6 by antigen-presenting cells and suppressed expression of interferon gamma by natural killer T cells, promoting hepatocyte proliferation. Absence of IL-17-producing γδT cells or deletion of Dectin-1 prevented development of regenerative phenotypes in subsets of innate immune cells. This slowed liver regeneration and was associated with reduced expression of regenerative growth factors and cell cycle regulators. Conversely, exogenous administration of IL-17 family cytokines or Dectin-1 ligands promoted regeneration. More broadly, we found that γδT cells are required for inflammatory responses mediated by IL-17 and Dectin-1.
  
  
  CONCLUSIONS
  γδT cells regulate hepatic regeneration by producing IL-22 and IL-17, which have direct mitogenic effects on hepatocytes and promote a regenerative phenotype in hepatic leukocytes, respectively. Dectin-1 ligation is required for γδT cells to promote hepatic regeneration.
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York.
authors.forename: Raghavendra
authors.initials: R
authors.lastname: Rao
authors.affiliation: S. Arthur Localio Laboratory, Department of Cell Biology, New York University School of Medicine, New York, New York.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Graffeo
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York.
authors.forename: Rishabh
authors.initials: R
authors.lastname: Gulati
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York.
authors.forename: Mohsin
authors.initials: M
authors.lastname: Jamal
authors.affiliation: S. Arthur Localio Laboratory, Department of Cell Biology, New York University School of Medicine, New York, New York.
authors.forename: Suchithra
authors.initials: S
authors.lastname: Narayan
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York.
authors.forename: Constantinos P
authors.initials: CP
authors.lastname: Zambirinis
authors.affiliation: S. Arthur Localio Laboratory, Department of Cell Biology, New York University School of Medicine, New York, New York.
authors.forename: Rocky
authors.initials: R
authors.lastname: Barilla
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York.
authors.forename: Michael
authors.initials: M
authors.lastname: Deutsch
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York.
authors.forename: Stephanie H
authors.initials: SH
authors.lastname: Greco
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York.
authors.forename: Atsuo
authors.initials: A
authors.lastname: Ochi
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York.
authors.forename: Lena
authors.initials: L
authors.lastname: Tomkötter
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York.
authors.forename: Reuven
authors.initials: R
authors.lastname: Blobstein
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York.
authors.forename: Antonina
authors.initials: A
authors.lastname: Avanzi
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Tippens
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York.
authors.forename: Yisroel
authors.initials: Y
authors.lastname: Gelbstein
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York.
authors.forename: Eliza
authors.initials: E
authors.lastname: Van Heerden
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York; S. Arthur Localio Laboratory, Department of Cell Biology, New York University School of Medicine, New York, New York. Electronic address: george.miller@nyumc.org.
authors.forename: George
authors.initials: G
authors.lastname: Miller
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D054418:Chemokine CCL20 / Q000378:metabolism; D005838:Genotype; D006498:Hepatectomy; D022781:Hepatocytes / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D037181:Lectins, C-Type / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000378:metabolism* / Q000601:surgery; D008115:Liver Regeneration; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors; D000097043:Interleukin-22; D000099181:Dectin-1
chemical_list: D054418:Chemokine CCL20; D018836:Inflammation Mediators; D007371:Interferon-gamma; D020381:Interleukin-17; D015850:Interleukin-6; D007378:Interleukins; D037181:Lectins, C-Type; D016692:Receptors, Antigen, T-Cell, gamma-delta; D000097043:Interleukin-22; D000099181:Dectin-1; C493447:CCL20 protein, mouse; C546929:CLEC7A protein, human; C577686:interleukin-6, mouse
keywords: IL-22; Inflammation; Kupffer Cells; NKT Cells