Hepatic Natural Killer T-Cell and CD8+ T-Cell Signatures in Mice with Nonalcoholic Steatohepatitis

Hepatic inflammation is a key pathologic feature of nonalcoholic steatohepatitis (NASH). Natural killer T (NKT) cells and clusters of differentiation (CD)8+ T-cells are known to play an important role in obesity-related adipose tissue inflammation. We hypothesized that these same inflammatory phenotypes would be present in progressive NASH. We used a previously established high-fat high-carbohydrate (HFHC) murine obesogenic diet model of progressive NASH to investigate the role of NKT cells and CD8+ T-cells in C57Bl6/J mice. To better understand the impact of these cell populations, CD1d-deficient and CD8+ T-cell-depleted mice were subjected to an HFHC diet for 16 weeks. C57Bl6/J mice fed an HFHC diet had increased body weight, liver triglyceride content, serum alanine aminotransferase levels, and increased NKT-cell and CD8+ T-cell infiltration in the liver. In addition, human liver sections from patients with NASH showed increased CD8+ T-cells. In comparison, CD1d-deficient and CD8 T-cell-depleted mice fed an HFHC diet had a lower hepatic triglyceride content, lower alanine aminotransferase levels, lower activated resident macrophages and infiltrating macrophages, improved nonalcoholic fatty liver disease activity scores, and reduced a-smooth muscle actin, collagen type 1 alpha 1, and collagen type 1 alpha 2 messenger RNA expression. Further, while CD1d-deficient mice were protected against weight gain on the HFHC diet, CD8 T-cell-depleted mice gained weight on the HFHC diet. Conclusion: We found that NASH has an immunological signature that includes hepatic infiltrating NKT and CD8+ T-cells. Depletion of these cells resulted in reduced NASH progression and thus presents novel therapeutic avenues for the treatment of NASH.