Mechanisms of T Cell Death in the Liver: To Bim or Not to Bim?

Abstract

Despite being a non-lymphoid organ, the liver displays immunological properties distinct from other solid organs and is associated with the induction of T cell tolerance. This property has been demonstrated in several clinical settings including transplantation and hepatotropic viral infections, such as those induced by hepatitis B and C viruses. Many models have been proposed to explain the ‘liver tolerance effect’, but the molecular and cellular mechanism(s) mediating this phenomenon remain unknown. Using transgenic mouse models, we have previously shown that the liver is the only non-lymphoid organ able to retain and activate naïve CD8+ T cells independently of lymphoid tissues in an antigen-specific manner. These findings, confirmed by other groups, have opened new possibilities to explain the remarkable capacity of the liver to induce antigen-specific tolerance in transplantation and following infection by hepatotropic viruses, such as the hepatitis C and B viruses. In our models, T cells activated by hepatocytes that proliferate die by neglect in a Bim-dependent manner. This paper will thus review the evidence showing Bim playing a critical role following intrahepatic primary T cell activation.

Durable Adoptive Immunotherapy for Leukemia Produced by Manipulation of Multiple Regulatory Pathways of CD8+ T-Cell Tolerance

“…The outcome of a T cell response is influenced greatly by signals received from antigen presenting cells (APC) engaged during priming, which often provide cytokines and co-stimulation that induce appropriate activation and differentiation (40). Healthy hepatocytes in Alb:Gag mice likely fail to provide such signals, contributing to T cell tolerance and deletion (4, 36). However, the requirement for activated APC can be by-passed by providing inflammatory signals, leading to T cell activation and memory formation even in the absence of some co-stimulatory molecules (41, 42).…”

Leukocyte Bim deficiency does not impact atherogenesis in ldlr −/− mice, despite a pronounced induction of autoimmune inflammation

“…In contrast, bim −/− livers displayed progressive leukocyte infiltrates highly enriched in T cells. Hepatocytes have the ability to prime naïve T cells, and the survival of liver-residing T cells is largely dependent on Bim 42 . The liver functions as a master regulator of cholesterol metabolism, and chronic steatohepatitis could conceivably lead to disturbances of lipid homeostasis in blood.…”

Persistent hepatitis C virus (HCV) infection impairs HCV‐specific cytotoxic T cell reactivity through Mcl‐1/Bim imbalance due to CD127 down‐regulation

“…The procedure of T cell death during chronic viral infection is determined by a carefully balanced and complex group of pro‐ and anti‐apoptotic proteins of the Bcl‐2 family, such as Bim and Mcl‐1 [10]. Bim is clearly involved in intrahepatic‐specific CTL apoptosis in animal models [16].…”

“…Bim is clearly involved in intrahepatic‐specific CTL apoptosis in animal models [16]. Bim is thought to act principally by activating Bax, permitting mitochondrial release of cytochrome c , which activates caspases, ultimately leading to cell death [10]. Expression of Bim is up‐regulated in human T cells in response to TCR triggering by the protein kinase C (PKC) and calcineurin pathways [17].…”

“…Passive T cell death, or death by cytokine deprivation, is controlled by members of the Bcl‐2 family, such as Bim and Mcl‐1. In experimental models, Bim carries out a pro‐apoptotic role in intrahepatic T cells that is counteracted by the Mcl‐1 action [10,11]. Interestingly, a role of Bim level on HCV‐specific CTL reactivity, according to CD127 expression, has been suggested recently by our group but this pathway has not been described in depth [5].…”