NKT cell activation influences hepatic immunity by interfering with cross-presentation in liver sinusoidal endothelial cells

Natural Killer T (NKT) cells are a predominant lymphoid cell population in the liver. They are specifically recruited to the liver via CXCR6 and migrate through the liver sinusoids along liver sinusoidal endothelial cells (LSEC). We have previously shown that LSEC can cross-present soluble antigens on MHC I molecules to CD8 T cells causing a functionally inert state. We now show that LSEC express CD1d and can present the model antigen α-galactosyl-ceramide (αGC) to NKT cells, leading to CD1-restricted NKT cell activation and cytokine production. CD1-restricted NKT activation in vivo led to reduced cross-presentation by LSEC, which was mediated in vitro by IFNγ, TNFα and prostaglandins, factors known to be produced by NKT cells. Reduced cross-presentation did not alter the immune modulatory capacity of LSEC towards the inactivation of naïve CD8 T cells, nor did the interaction with activated NKT cells in vivo convert LSEC into professional antigen presenting cells causing T cell activation. NKT activation in vivo reduced cross-presentation by LSEC and thereby compromised immune surveillance of effector CD8 T cells to control viral infection through the non-canonical CD8 T cell effector function triggered by cross-presentation. Thus, NKT cell activation in the liver influences hepatic immune responses by interfering with the antigen-presenting function of LSEC.