Interleukin 17-Producing γδT Cells Promote Hepatic Regeneration in Mice

BACKGROUND & AIMS: Subsets of leukocytes synergize with regenerative growth factors to promote hepatic regeneration. gamma delta T cells are early responders to inflammation-induced injury in a number of contexts. We investigated the role of gamma delta T cells in hepatic regeneration using mice with disruptions in Tcrd (encodes the T-cell receptor delta 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. gamma delta T 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 gamma delta T cells and their increased production of interleukin (IL)-17 family cytokines. Recruited gamma delta T 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 gamma delta T 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 gamma delta T cells are required for inflammatory responses mediated by IL-17 and Dectin-1. CONCLUSIONS: gamma delta T 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 gamma delta T cells to promote hepatic regeneration.