Augmentation of Vα14 Nkt Cell–Mediated Cytotoxicity by Interleukin 4 in an Autocrine Mechanism Resulting in the Development of Concanavalin a–Induced Hepatitis

Abstract

The administration of concanavalin A (Con A) induces a rapid severe injury of hepatocytes in mice. Although the Con A–induced hepatitis is considered to be an experimental model of human autoimmune hepatitis, the precise cellular and molecular mechanisms that induce hepatocyte injury remain unclear. Here, we demonstrate that Vα14 NKT cells are required and sufficient for induction of this hepatitis. Moreover, interleukin (IL)-4 produced by Con A–activated Vα14 NKT cells is found to play a crucial role in disease development by augmenting the cytotoxic activity of Vα14 NKT cells in an autocrine fashion. Indeed, short-term treatment with IL-4 induces an increase in the expression of granzyme B and Fas ligand (L) in Vα14 NKT cells. Moreover, Vα14 NKT cells from either perforin knock-out mice or FasL-mutant gld/gld mice fail to induce hepatitis, and hence perforin–granzyme B and FasL appear to be effector molecules in Con A–induced Vα14 NKT cell–mediated hepatocyte injury.

Concanavalin A-mediated T cell proliferation is regulated by herpes virus entry mediator costimulatory molecule

“…ConA has been extensively used in the model of autoimmune hepatitis and CD4 + T cells as well as NKT cells were suggested to play a role in this model (Kaneko et al 2000;Tiegs et al 1992;Toyabe et al 1997;Yang et al 2010). In addition, ConA has been reported to show anti-tumor effects, which are mediated by the intrahepatic activation of both NK cells (Miyagi et al 2004) and CD8 + T cells (Chang et al 2007;Lei and Chang 2009).…”

Invariant Vα14+ NKT Cells Participate in the Early Response to EntericListeria monocytogenesInfection

“…V␣14 ϩ NKT have been implicated in a number of immunemediated pathologies including graft-vs-host disease, autoimmune hepatitis, and in fetal loss (17)(18)(19). In addition, a disease-controlling role for NKT cells has been shown in V␣14-J␣18 transgenic (Tg) 5 nonobese diabetic mice (20).…”

The Bile Acid Sensor Farnesoid X Receptor Is a Modulator of Liver Immunity in a Rodent Model of Acute Hepatitis

“…Following Con A administration, liver histology shows massive granulocyte accumulation, CD4 ϩ T cell infiltration, and hepatocyte necrosis/apoptosis (3,4). The induction of this hepatitis depends on CD1d-restricted invariant NKT cells, that express an invariant V␣14J␣18 TCR (5,6). Thus, J␣18 Ϫ/Ϫ and CD1d Ϫ/Ϫ mice that lack NKT cells are resistant to Con A-induced hepatic injury (5,6), whereas the adoptive transfer of NKT cells isolated from wild-type (WT) 3 mice into healthy CD1d Ϫ/Ϫ or J␣18 Ϫ/Ϫ mice restores hepatic injury mediated by Con A.…”

“…The induction of this hepatitis depends on CD1d-restricted invariant NKT cells, that express an invariant V␣14J␣18 TCR (5,6). Thus, J␣18 Ϫ/Ϫ and CD1d Ϫ/Ϫ mice that lack NKT cells are resistant to Con A-induced hepatic injury (5,6), whereas the adoptive transfer of NKT cells isolated from wild-type (WT) 3 mice into healthy CD1d Ϫ/Ϫ or J␣18 Ϫ/Ϫ mice restores hepatic injury mediated by Con A. Previous studies have shown that Con A activates hepatic resident NKT cells to produce IL-4 (5, 6); IL-4, in turn, acts on NKT cells in an autocrine fashion to induce Fas ligand (FasL) expression on these cells, which subsequently promotes hepatocyte cell death (i.e., cytotoxicity), possibly by interacting with Fas-expressing hepatocytes.…”