The role of intrahepatic CD3+/CD4−/CD8− double negative T (DN T) cells in enhanced acetaminophen toxicity

Abstract

The role of the immune system, specifically NK, NKT and CD3 cells, in acetaminophen (APAP) induced liver injury remains inconsistently defined. In the present study, wild type (C57BL/6J) mice and granzyme B deficient (GrB −/−) mice were treated with acetaminophen to assess the role of the immune system in acute liver injury. Doses of acetaminophen that induced sub lethal liver injury in wild type mice unexpectedly produced fatal hepatotoxicity in granzyme B deficient (GrB −/−) mice. Analysis revealed that GrB −/− mice had an increased population of intrahepatic CD3 (+), CD4 (−), CD8 (−) lymphocytes expressing the CD69 activation marker and Fas Ligand. Depletion of these cells in the GrB −/− and wild type mice made them less susceptible to APAP injury, while depletion of NK1.1 (+) cells or both CD4 (+) and CD8 (+) T cells failed to provide the same hepatoprotection. Transfer of the GrB −/− IHLs further exacerbated liver injury and increased mortality in wild type mice but not in LRP/LPR mice, lacking fas expression. Conclusions Acetaminophen toxicity is enhanced by the presence of activated, FasL expressing intrahepatic CD3 (+), CD4 (−), CD8 (−), NK1.1 (−) T cells. Depletion of these cells from GrB −/− mice and wild type mice greatly reduces mortality and improves the course of liver injury recovery.

CD3+CD4-CD8- (Double-Negative) T Cells in Inflammation, Immune Disorders and Cancer

“…TCRαβ + DN T cells comprise one-third of normal intraepithelial lymphocytes in the murine gut, and gut-resident DN T cells have phenotypes similar to those of peripheral DN T cells in mice ( 13 , 14 ). A significant proportion of hepatic DN T cells is found in normal murine and human liver tissue, and DN T cells accelerate murine acetaminophen toxicity by expressing the activation marker CD69 and Fas ligand (FasL) ( 15 , 16 ). DN T cells were reported to reside as preactivated tissue resident memory-like cells in the lung parenchyma, expressing the memory markers CD44, CD11a and CD103, and the cytotoxic effector molecule FasL; therefore, resident memory DN T cells expand rapidly to protect against influenza A virus infection ( 17 ).…”

The decrease in number of splenic lymphocytes in mice fed Rhodiola kirilowii during pregnancy and lactation concerns mainly CD19+ and CD4+ cells

“…Moreover, the CD3+ CD4-, CD8- population was found in the states of pathological activation of the immune system. Increased size of this population was noted in granzyme B deficient (GrB –/–) mice after acetaminophen liver injury [ 25 ]. It also could be induced in vitro after 4-5 times stimulation of CD4+ T cells (which mimics chronic immune hyper-activation) [ 26 ].…”

Natural Killer T Cells in Various Mouse Models of Hepatitis

“…The liver is an important organ of drug metabolism, and it is more susceptible to damage due to the toxicity of the drugs themselves or their metabolites. Drug-induced liver injury, especially acetaminophen ( N -acetyl-p-aminophenol, APAP) overdose, is the most common cause of acute liver failure in Western countries [ 32 – 34 ]. N -acetyl-p-benzoquinone-imine (NAPQI) is a toxic metabolite of APAP that can combine with glutathione for detoxification.…”

“…The difference was primarily found in ketone bodies and CYP2E1, suggesting that NKT cells may be closely related to metabolism [ 38 ]. In addition, granzyme B-deficient mice can experience aggravated liver damage through an increased number and greater activation of NK and NKT cells, as well as FasL expression [ 32 ].…”