γδ T Cells Promote Steatohepatitis by Orchestrating Innate and Adaptive Immune Programming

Abstract

Background and Aims The recruitment and activation of inflammatory cells in the liver delineates the transition from hepatic steatosis to steatohepatitis (SH). Approach and Results We found that in SH, γδT cells are recruited to the liver by C‐C chemokine receptor (CCR) 2, CCR5, and nucleotide‐binding oligomerization domain‐containing protein 2 signaling and are skewed toward an interleukin (IL)‐17A+ phenotype in an inducible costimulator (ICOS)/ICOS ligand–dependent manner. γδT cells exhibit a distinct Vγ4+, PD1+, Ly6C+CD44+ phenotype in SH. Moreover, γδT cells up‐regulate both CD1d, which is necessary for lipid‐based antigens presentation, and the free fatty acid receptor, CD36. γδT cells are stimulated to express IL‐17A by palmitic acid and CD1d ligation. Deletion, depletion, and targeted interruption of γδT cell recruitment protects against diet‐induced SH and accelerates disease resolution. Conclusions We demonstrate that hepatic γδT cells exacerbate SH, independent of IL‐17 expression, by mitigating conventional CD4+ T‐cell expansion and modulating their inflammatory program by CD1d‐dependent vascular endothelial growth factor expression.

γδT Cells and CD1d, Novel Immune Players in Alcoholic and Nonalcoholic Steatohepatitis?

“…(10) Torres-Hernandez and Wang et al discovered that γδ T cells in steatohepatitis express high CD1d, which plays an important role in regulating the expression of many inflammatory mediators, thereby promoting steatohepatitis. (5) As discussed previously, immune cells play important roles in the pathogenesis of steatohepatitis. However, how to best target immune cells to improve steatohepatitis remains a challenge.…”

“…In this issue of Hepatology, Torres-Hernandez and Wang et al provided evidence suggesting that gammadelta (γδ) T cells connect innate and adaptive immune cells to promote steatohepatitis, highlighting an important role of γδ T cells in the pathogenesis of steatohepatitis. (5) γδ T cells, a bridge between the innate and adaptive immune system, are capable of modulating liver disease progression. (6) The γδ T cells, which belong to a unique T-cell subset, differ from classic αβ T cells by expressing γδ T-cell receptor instead of αβ T-cell receptor, and make up 15%-25% of total hepatic T cells, although its circulating percentage accounts for only 2%-10% of total T cells.…”

“…However, how these immune cells work together to modulate ASH and NASH still remains poorly understood. In this issue of H epatology , Torres‐Hernandez and Wang et al provided evidence suggesting that gammadelta (γδ) T cells connect innate and adaptive immune cells to promote steatohepatitis, highlighting an important role of γδ T cells in the pathogenesis of steatohepatitis …”

“…In this issue of H epatology , by using ASH (chronic‐plus‐binge ethanol feeding), NASH (methionine‐choline deficient diet feeding), and a combination model (HFD‐plus‐binge ethanol feeding), Torres‐Hernandez and Wang et al extensively characterized the role of γδ T cells in the development of steatohepatitis . They found that hepatic γδ T‐cell infiltration was elevated in all three models of steatohepatitis, and such γδ T‐cell expansion was dependent on CC motif chemokine receptor 2 and nucleotide binding oligomerization domain containing 2 signaling.…”

“…In addition, CD1d‐deficient mice demonstrated improved NASH progression on the HFHC diet . Torres‐Hernandez and Wang et al discovered that γδ T cells in steatohepatitis express high CD1d, which plays an important role in regulating the expression of many inflammatory mediators, thereby promoting steatohepatitis …”