Type I interferon responses drive intrahepatic T cells to promote metabolic syndrome

Abstract

Obesity-related insulin resistance is driven by low-grade chronic inflammation of metabolic tissues. In the liver, non-alcoholic fatty liver disease (NAFLD) is associated with hepatic insulin resistance and systemic glucose dysregulation. However, the immunological factors supporting these processes are poorly understood. We found that the liver accumulates pathogenic CD8+ T cell subsets which control hepatic insulin sensitivity and gluconeogenesis during diet-induced obesity in mice. In a cohort of human patients, CD8+ T cells represent a dominant intrahepatic immune cell population which links to glucose dysregulation. Accumulation and activation of these cells are largely supported by type I interferon (IFN-I) responses in the liver. Livers from obese mice upregulate critical interferon regulatory factors (IRFs), interferon stimulatory genes (ISGs), and IFNα protein, while IFNαR1−/− mice, or CD8-specific IFNαR1−/− chimeric mice are protected from disease. IFNαR1 inhibitors improve metabolic parameters in mice, while CD8+ T cells and IFN-I responses correlate with NAFLD activity in human patients. Thus, IFN-I responses represent a central immunological axis that governs intrahepatic T cell pathogenicity during metabolic disease.

Pathogenesis of Nonalcoholic Steatohepatitis: An Overview

“…In mice and humans, cytotoxic CD8+ T cells accumulate in the liver during NAFLD, and their pharmacologic or genetic ablation results in decreased steatosis, IR, inflammation, and hepatic stellate cell activation. Activation of these cytotoxic CD8+ T cells is supported by type I IFN responses and leads to the production of the proinflammatory cytokines IFNγ and TNFα . Cytotoxic CD8+ T cells have also been shown to promote NASH development and subsequent transition to HCC in a process that requires crosstalk with natural killer T cells.…”

“…In mice and humans, cytotoxic CD8+ T cells accumulate in the liver during NAFLD, and their pharmacologic (84) or genetic ablation (85) results in decreased steatosis, IR, inflammation, and hepatic stellate cell activation. Activation of these cytotoxic CD8+ T cells is supported by type I IFN responses and leads to the production of the proinflammatory cytokines IFNγ and TNFα.…”

“…Activation of these cytotoxic CD8+ T cells is supported by type I IFN responses and leads to the production of the proinflammatory cytokines IFNγ and TNFα. (85) Cytotoxic CD8+ T cells have also been shown to promote NASH development and subsequent transition to HCC in a process that requires crosstalk with natural killer T cells.…”

Foundations of Immunometabolism and Implications for Metabolic Health and Disease

“…It is interesting to note that within the adipose tissue environment the T cell receptor repertoire shows significant bias in CD4 + T cells, which supports the possibility that specific antigens presented only in the adipose environment may lead to clonal expansion (Morris et al, 2013). Interestingly, CD8 + T cells have been shown to accumulate in the livers of obese mice and contribute to the development of metabolic dysfunction, but their accumulation and activation is believed to occur in response to interferon signaling, rather the presence of a specific antigen (Ghazarian, 2017). Identification of the tissue-specific differences in inflammatory activation may allow better dissection of functional programming of immune effectors associated with metabolic tissue inflammatory state.…”

The Fat of the Matter: Obesity and Visceral Adiposity in Treated HIV Infection

“…Although the exact mechanisms are not well understood, there may be several contributing factors not common among HIV-uninfected persons. First, HIV infection is characterized by persistent inflammation and immune activation[77], which 1) could help explain higher rates of NASH and liver disease severity in HIV infection (63% vs 37% in HIV-uninfected)[78] and 2) contributes to greater insulin resistance, furthering metabolic dysregulation in both adipose tissue and the liver[79, 80]. In addition to traditional risk factors (older age, sedentary lifestyle), HIV-/ART-specific factors (dyslipidemia, microbial translocation, mitochondrial dysfunction) likely contribute.…”