TLR3 Signaling in iNKT cell Promotes Apoptosis of γδ T cells (134.27)

Abstract

Abstract Polyinosinic-polycytidylic acid (poly I:C, a specific ligand for TLR3) activate immune cells (such as DC and NK cell) in a TLR3-dependent manner to induce cytokine production. TLR3 expression by iNKT cells has not been determined. The main objective of this study was to determine TLR3 expression by iNKT cell and their functional responsiveness after stimulation with poly I:C. We hypothesize that TLR3 signaling in iNKT cells suppress γδT cell functions by induction of apoptosis. Our hypothesis is based on the following observations: First, poly I:C administration into C57BL6 mice was associated with extracellular TLR3 and intracellular cytokine (IFN-γ and TNF-α) expression by hepatic iNKT cells. Second, activated hepatic iNKT cells promote apoptosis of γδT cells via induction of IFN-γ and TNF-α since pretreatment of C57BL6 mice with anti-TNF-α or anti-IFN-γ Abs prior to poly I:C administration caused a significant decrease in the frequency of active caspase 3 expression by hepatic γδT cells. Finally, the frequency of γδT cells accumulation in the liver was significantly increased by iNKT cell deficiency (vs. WT mice) after poly I:C administration. Moreover, hepatic γδT cells derived from iNKT cell KO mice were resistant to apoptotic death (and thus associated with increased survival) relative to hepatic γδT cells derived from WT mice post-poly I:C administration. It is noteworthy that serum levels of TNF-α and IFN-γ were also ablated by iNKT cell deficiency. In summary, our results support the notion that (i) hepatic iNKT cells directly respond to TLR3 signaling to activate γδT cells; (ii) the activation depends on cell-cell contact whereby iNKT cell-derived cytokines induce the programmed cell death of γδT cells; an effect that may attenuate potential effector functions of γδT cells.