Liver-primed memory T cells generated under noninflammatory conditions provide anti-infectious immunity

Development of CD8⁺⁺ T cell (CTL) immunity or tolerance is linked to the conditions during T cell priming. Dendritic cells (DCs) matured during inflammation generate effector/memory T cells, whereas immature DCs cause T cell deletion/anergy. We identify a third outcome of T cell priming in absence of inflammation enabled by cross-presenting liver sinusoidal endothelial cells. Such priming generated memory T cells that were spared from deletion by immature DCs. Similar to central memory T cells, liver-primed T cells differentiated into effector CTLs upon antigen re-encounter on matured DCs even after prolonged absence of antigen. Their reactivation required combinatorial signaling through the TCR, CD28, and IL-12R and controlled bacterial and viral infections. Gene expression profiling identified liver-primed T cells as a distinct Neuropilin-1⁺⁺ memory population. Generation of liver-primed memory T cells may prevent pathogens that avoid DC maturation by innate immune escape from also escaping adaptive immunity through attrition of the T cell repertoire. Development of T. cell immunity and memory is believed to occur exclusively in the context of inflammation. Knolle and colleagues demonstrate the existence of an alternative pathway of memory T. cell formation in the absence of inflammation. Such T. cell memory was generated not by classical antigen-presenting cells, such as dendritic cells, but by organ-resident endothelial cells in the liver and contributes to infection control. Generation of liver-primed memory T. cells counteracts immune escape of pathogens that circumvent induction of inflammation.