Liver sinusoidal endothelial cells (LSECs) are prominent liver-resident antigen (cross-)presenting cells. LSEC cross-priming of naïve CD8 T cells does not require CD4 T cell help in contrast to priming by dendritic cells (DC) but leads to formation of memory T cells that is preceded by transient GzmB expression. Here we provide evidence for a so far unrecognized CD4 T helper cell-function in LSEC-induced CD8 T cell-activation.