The Detrimental Role of Regulatory T Cells in Nonalcoholic Steatohepatitis

Abstract

Nonalcoholic steatohepatitis (NASH) is induced by steatosis and metabolic inflammation. While involvement of the innate immune response has been shown, the role of the adaptive immune response in NASH remains controversial. Likewise, the role of regulatory T cells (Treg) in NASH remains unclear although initial clinical trials aim to target these regulatory responses. High‐fat high‐carbohydrate (HF‐HC) diet feeding of NASH‐resistant BALB/c mice as well as the corresponding recombination activating 1 (Rag)‐deficient strain was used to induce NASH and to study the role of the adaptive immune response. HF‐HC diet feeding induced strong activation of intrahepatic T cells in BALB/c mice, suggesting an antigen‐driven effect. In contrast, the effects of the absence of the adaptive immune response was notable. NASH in BALB/c Rag1−/− mice was substantially worsened and accompanied by a sharp increase of M1‐like macrophage numbers. Furthermore, we found an increase in intrahepatic Treg numbers in NASH, but either adoptive Treg transfer or anti‐cluster of differentiation (CD)3 therapy unexpectedly increased steatosis and the alanine aminotransferase level without otherwise affecting NASH. Conclusion: Although intrahepatic T cells were activated and marginally clonally expanded in NASH, these effects were counterbalanced by increased Treg numbers. The ablation of adaptive immunity in murine NASH led to marked aggravation of NASH, suggesting that Tregs are not regulators of metabolic inflammation but rather enhance it.

T cells: Friends and foes in NASH pathogenesis and hepatocarcinogenesis

“…[ 73 ] Recent findings in HFHC nutritional murine models indicate that Treg frequency increases in the NASH liver, which might counterbalance the CD8 + T‐cell effector proportion. [ 74 ] However, adoptive transfer of Tregs in mice lacking B‐ and T‐lymphocytes (Rag1 –/– ) failed to rescue the aggravation of inflammation observed upon high caloric feeding. Indeed, Treg transfer seemed to exacerbate the metabolic phenotype.…”

T Cell Subsets and Natural Killer Cells in the Pathogenesis of Nonalcoholic Fatty Liver Disease

“…A study that investigated the effect of inducing Tregs using the immunosuppressant OKT3 in NASH patients found that immune parameters and liver function were improved [43]. Another recent study that found increased intrahepatic Tregs in mice NASH models also reported their detrimental roles [44]. However, further studies are required to elucidate the detailed mechanisms for their roles which can help their applications in the immunotherapy of NASH.…”

Implications of regulatory T cells in non-lymphoid tissue physiology and pathophysiology

“…Similar to their orchestrating role in sterile inflammation in the VAT, hepatic Treg cells have also been implicated in the context of non-alcoholic steatohepatitis (NASH). High-fat and high-carbohydrate diets, which can induce NASH, were associated with an increased number and proliferation rate of Treg cells in the liver (123). This was mirrored by increased fractions of IFNg and TNFa expressing T cells in the total hepatic CD4 + T cell compartment (123).…”

“…High-fat and high-carbohydrate diets, which can induce NASH, were associated with an increased number and proliferation rate of Treg cells in the liver (123). This was mirrored by increased fractions of IFNg and TNFa expressing T cells in the total hepatic CD4 + T cell compartment (123). Notably, adoptive transfer of Treg cells to mice post-feeding them a high-fat, high-sugar diet exacerbated liver steatosis and liver cell injury (123,124).…”