Interleukin 17-producing γδT cells promote hepatic regeneration in mice

Gastroenterology. 2014 Aug;147(2):473-84.e2. doi: 10.1053/j.gastro.2014.04.042. Epub 2014 May 4.

Abstract

Background & aims: 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.

Keywords: IL-22; Inflammation; Kupffer Cells; NKT Cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Proliferation*
  • Cells, Cultured
  • Chemokine CCL20 / metabolism
  • Genotype
  • Hepatectomy
  • Hepatocytes / immunology
  • Hepatocytes / metabolism*
  • Humans
  • Inflammation Mediators / metabolism*
  • Interferon-gamma / metabolism
  • Interleukin-17 / metabolism*
  • Interleukin-6 / metabolism
  • Interleukins / metabolism
  • Lectins, C-Type / deficiency
  • Lectins, C-Type / genetics
  • Lectins, C-Type / metabolism
  • Liver / immunology
  • Liver / metabolism*
  • Liver / surgery
  • Liver Regeneration*
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phenotype
  • Receptors, Antigen, T-Cell, gamma-delta / deficiency
  • Receptors, Antigen, T-Cell, gamma-delta / genetics
  • Receptors, Antigen, T-Cell, gamma-delta / metabolism*
  • Signal Transduction
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism*
  • Time Factors

Substances

  • CCL20 protein, mouse
  • CLEC7A protein, human
  • Chemokine CCL20
  • Inflammation Mediators
  • Interleukin-17
  • Interleukin-6
  • Interleukins
  • Lectins, C-Type
  • Receptors, Antigen, T-Cell, gamma-delta
  • dectin 1
  • interleukin-6, mouse
  • Interferon-gamma
  • interleukin-22