The immunoregulatory effects of CD8 T‐cell–derived perforin on diet‐induced nonalcoholic steatohepatitis

Abstract

The liver is a central immunologic organ with a high density of myeloid and lymphoid immune cells that play important roles in the development and progression of nonalcoholic steatohepatitis (NASH). However, the immune‐cell–mediated regulation of NASH and its underlying mechanisms remain obscure. In this study, Prf1null mice showed significantly higher plasma alanine transaminase levels, with increased liver fat accumulation, lobular inflammation, and focal necrosis compared with wild‐type (WT) mice after 4 wk of feeding on a methionine‐ and choline‐deficient diet (MCD) or 16 wk of feeding on a high‐fat diet. Perforin deficiency promoted the M1 polarization of infiltrated monocytes. Moreover, MCD‐fed Prf1null mice exhibited increased accumulation, survival, activation, and proinflammatory cytokine production of CD8 T cells but not NK cells or CD4 T cells. Adoptive transfer of CD8 T cells or NK cells from WT or Prf1null mice, together with non‐CD8 cells or non‐NK cells from WT mice, indicated that CD8 T‐cell–derived perforin participates in the mechanism regulating liver inflammation and thus plays a protective role in the development of NASH. Perforin‐deficient CD8 T cells exhibited decreased cytotoxicity toward bone marrow‐derived M1 monocytes and macrophages. According to the RNA sequencing data, the perforin deficiency inhibited cell apoptosis and enhanced the activation, migration, and proinflammatory cytokine production of CD8 T cells in mice with NASH. Furthermore, we found higher plasma soluble perforin levels and hepatic perforin expression in NASH patients, suggesting clinical relevance of the findings. We have elucidated an important role for the cytotoxic immune effector molecule perforin from CD8 T cells in restricting hepatic inflammation in mice with NASH and suggest that therapies designed to maximize the function of endogenous perforin in CD8 T cells might have potential benefits as NASH treatments.—Wang, T., Sun, G., Wang, Y., Li, S., Zhao, X., Zhang, C., Jin, H., Tian, D., Liu, K., Shi, W., Tian, Y., Zhang, D. The immunoregulatory effects of CD8 T‐cell–derived perforin on diet‐induced nonalcoholic steatohepatitis. FASEB J. 33, 8490–8503 (2019). http://www.fasebj.org

Integrated Analysis of the ETS Family in Melanoma Reveals a Regulatory Role of ETV7 in the Immune Microenvironment

“…PRF1 encodes the protein perforin, which is present in T and NK cells and facilitates the release of granzymes and subsequent cytolysis of target cells ( 61 ). CCR5, CXCL10, CXCR3, CXCL9, CCL5, and IFNG also participate in the migration, trafficking, or differentiation of T cells ( 61 – 65 ). Whether ETV7 binds the promoter of these genes and stimulates their expression remains unknown, but our analysis showed a high correlation between them and ETV7 at the transcriptional level.…”

Immunological mechanisms and therapeutic targets of fatty liver diseases

“…258 Other studies have shown that Tc cell-derived perforin participates in the mechanism regulating liver inflammation and thus plays a protective role in the development of NASH. 259 In addition, a recent study revealed that Tc cells interact synergistically with NKT cells to promote the progression of NASH and increase the incidence of NASH-related HCC. 257 NKT cells.…”

Perforin Acts as an Immune Regulator to Prevent the Progression of NAFLD

“…Perforin has also been reported to play critical roles in promoting inflammation-mediated diseases, including type 1 diabetes (33), cerebral malaria (34), and viral myocarditis (35). A recent study revealed that perforin expressed in CD8 T cells regulates innate and adaptive immunity in the liver and exerts a protective effect in MCD (methionine/choline-deficient diet) diet-induced NASH models (36). Interestingly, MCD dietinduced non-obese NAFLD displays characteristics distinct from those of obesity-induced NAFLD.…”