γδT Cells and CD1d, Novel Immune Players in Alcoholic and Nonalcoholic Steatohepatitis?
Authors: Xiaolin Wang, Bin Gao
Journal: Hepatology (2019)

This work was supported by the intramural program of NIAAA, NIH (B.G.). Potential conflict of interest: Nothing to report. See Article on Page 477 Alcoholic and nonalcoholic fatty liver diseases (NALFD) have emerged as the leading causes of chronic liver diseases worldwide, having a similar continuum of disorders ranging from simple steatosis to steatohepatitis, cirrhosis, and hepatocellular carcinoma. Inflammation plays an important role in controlling alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH) development and progression, but the exact contribution of immune cells that triggers progression from simple steatosis to steatohepatitis is still obscure.1 Neutrophils have long been noted as common infiltrating cells in steatohepatitis, playing an important role in the progression of ASH and NASH through the production of proinflammatory mediators, generation of reactive oxygen species (ROS) and the release of granule proteins. A recent study suggests that neutrophil infiltration is an initiating event in the development of NASH through the formation of neutrophil extracellular traps, which is followed by monocyte‐derived macrophage infiltration and inflammatory cytokine production.2 ASH and NASH are also associated with the activation of Kupffer cells (KCs) (liver resident macrophages) and infiltrating macrophages, and the functions of both types of macrophages in steatohepatitis have been studied extensively. KCs are known to be involved in the initiation of inflammatory responses in the early stages of NASH by secreting cytokines and chemokines and recruiting blood‐derived monocytes and bone marrow–derived neutrophils into the liver, thereby driving fatty liver progression to steatohepatitis. McGettigan et al.3 recently demonstrated that dietary fat and cholesterol synergistically altered the transcription and phenotype of KCs by inducing matrix remodeling and lipid metabolism genes and suppressing type 1 cytokine transcription. Type 2 cytokines acted as upstream regulators that drive the phenotype change of KCs from proinflammatory to tissue repair and regeneration. Moreover, KCs and infiltrating macrophages have distinct lipid processes and transcriptional profiles in the pathogenesis of steatohepatitis.3 CD1d‐restricted natural killer T cells (NKTs) have also been shown to play an important role in inflammatory conditions, but their functions in steatohepatitis were just recently divulged. It was observed that hepatic infiltrating NKT cells were increased and activated in several models of NASH. These activated NKT cells and CD8+ T cells cooperatively induce liver damage in steatohepatitis through interactions with hepatocytes.4 Collectively, many studies have suggested that both innate and adaptive immune cells play an important role in modulating the pathogenesis and progression of steatohepatitis. However, how these immune cells work together to modulate ASH and NASH still remains poorly understood. 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. The γδ T cells respond rapidly to inflammation by recognizing danger‐associated molecular patterns and pathogen‐associated molecular patterns through the secretion of immunomodulatory cytokines, including interleukin (IL)‐17, interferon‐γ, and transforming growth factor β. The γδ T cells showed a protective role in Con A–induced hepatitis by negatively regulating the functions of NKT cells in an IL‐17A‐dependent manner.6 The recruitment of γδ T cells plays a role in promoting liver regeneration after partial hepatectomy by producing IL‐22 and IL‐17.6 By using multidrug resistance gene 2 knockout mice in a model of cholestatic liver disease, Tedesco et al. demonstrated that the activation of γδ T cells and their production of IL‐17 were required in the development of liver inflammation and fibrosis.7 Recently, the involvement of γδ T cells in the progression of NAFLD has received attention. For example, Li et al. reported that the gut microbiota maintain homeostasis of liver IL‐17 producing γδ T cells in a lipid antigen/CD1d‐dependent manner, thereby promoting high‐fat/high‐carbohydrate diet (HFHCD)–induced or high‐fat diet (HFD)–induced NAFLD and liver damage.8 However, the exact role of γδ T cells in the pathogenesis of steatohepatitis is still not fully understood. In this issue of Hepatology, 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.5 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. Depletion of γδ T cells attenuated liver steatosis, leukocyte infiltration, and inflammation. The authors further demonstrated that the recruited γδ T cells exhibited increased IL‐17A expression and were the main source of IL‐17A in steatohepatitis. It has been reported that γδ T cell–mediated IL‐17 signaling propagates a cascade of events that accelerated NASH progression through neutrophil recruitment, inflammation, and ROS induction induced by HFHCD or HFD feeding.8 Surprisingly, Torres‐Hernandez and Wang et al. found that γδ T cells promoted steatohepatitis independent of IL‐17 signaling. The dispensability of IL‐17 between these studies is not clear and may be specific to the experimental models they studied. Instead, Torres‐Hernandez and Wang et al. provided evidence suggesting a mechanism that γδ T cells promote steatohepatitis by modulating conventional CD4+ T‐cell expansion and their inflammatory program through CD1d‐dependent vascular endothelial growth factor expression. CD1d is a major histocompatibility complex class I–like molecule with the capacity to present lipid antigens to NKT cells, thus enabling metabolic immunity. Recent studies have suggested that hepatocyte‐expressed CD1d, which presents microbiota lipid antigen, is responsible for IL‐17 production in liver γδ T cells.8 Hepatocyte‐specific deletion of CD1d revealed the importance of CD1d‐dependent regulation of liver iNKT cell in maintaining immune homeostasis.9 In addition, CD1d‐deficient mice demonstrated improved NASH progression on the HFHC diet.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. To our knowledge, there have been no reports on immunotherapy in ASH or NASH. Given an important role of CD1d in the regulation of γδ T cells, targeting CD1d and γδ T cells may have therapeutic potential for the treatment of steatohepatitis. Continuous efforts toward organization and regulation of the complex immune system in steatohepatitis may open new avenues for treatment of ASH and NASH in the future.