The Differential Roles of T Cells in Non-alcoholic Fatty Liver Disease and Obesity

Abstract

Non-alcoholic fatty liver disease (NAFLD) constitutes a spectrum of disease states characterized by hepatic steatosis and is closely associated to obesity and the metabolic syndrome. In non-alcoholic steatohepatitis (NASH), additionally, inflammatory changes and hepatocellular damage are present, representing a more severe condition, for which the treatment is an unmet medical need. Pathophysiologically, the immune system is one of the main drivers of NAFLD progression and other obesity-related comorbidities, and both the innate and adaptive immune system are involved. T cells form the cellular component of the adaptive immune system and consist of multiple differentially active subsets, i.e., T helper (Th) cells, regulatory T (Treg) cells, and cytotoxic T (Tc) cells, as well as several innate T-cell subsets. This review focuses on the role of these T-cell subsets in the pathogenesis of NAFLD, as well as the association with obesity and type 2 diabetes mellitus, reviewing the available evidence from both animal and human studies. Briefly, Th1, Th2, Th17, and Th22 cells seem to have an attenuating effect on adiposity. Th2, Th22, and Treg cells seem to decrease insulin resistance, whereas Th1, Th17, and Tc cells have an aggravating effect. Concerning NAFLD, both Th22 and Treg cells appear to have an overall tempering effect, whereas Th17 and Tc cells seem to induce more liver damage and fibrosis progression. The evidence regarding the role of the innate T-cell subsets is more controversial and warrants further exploration.

Keywords: T helper cells; cytotoxic T cells; natural killer T cells; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; obesity; regulatory T cells; type 2 diabetes mellitus.

Figure 1

Overview of the differential effects of the main T cell subsets in the pathophysiology of NAFLD : (A) Th1, (B) Th2, (C) Th17, (D) Th22, (E) Treg, (F) Tc and (G) NKT. Evidence was included in the figure exclusively when the effect was demonstrated in gain-of-function or loss-of-function experiments. ^#In the absence of TGF-β. ^§In the absence of IL-6.^†Invariant NKT cells express a semi-invariant TCRα chain (Vα14Jα18 in mice and Vα24Jα18 in humans). *In humans the natural killer cell marker CD56 is sometimes used. Neither CD56 nor NK1.1 is considered specific enough to characterize NKT cells. ¹Yet more adipose tissue inflammation. ²Not proven in the context of NAFLD. ³Conflicting evidence. ⁴Upon administration of high, non-physiologic doses of IL-22. ⁵To a minor extent. AHR, aryl hydrocarbon receptor; CD, cluster of differentiation; Foxp3, forkhead box P3; IL, interleukin; NKT, natural killer T cell; OPN, osteopontin; RA, retinoic acid; RORγt, RAR-related orphan receptor γt; Shh, Sonic Hedgehog; T-bet; Tc, cytotoxic T cell; Th1, T helper 1; Th2, T helper 2; Th17, T helper 17; Th22 T helper 22; Treg, regulatory T cell.

Figure 2

Proposed mechanisms for the interplay between the liver, adipose tissue and gut microbiome in obesity and NAFLD. The increased availability of a substance is depicted by an upwards arrow, the decreased availability by a downwards arrow. (A) Situation in health. (B) Situation in obesity and NAFLD. AC, adipocyte; ATM, adipose tissue macrophage; IFNγ, interferon γ; IL, interleukin; KC, Kupffer cell; LPS, lipopolysaccharide; SCFAs, short-chain fatty acids; TGFβ, transforming growth factor β; Tc, cytotoxic T cell; Th1, T helper 1 cell; Th17, T helper 17 cell; Th2, T helper 2 cell; Th22, T helper 22 cell; TNFα, tumor necrosis factor α; Treg, regulatory T cell.