Systematic investigation of Natural Killer cell stimulation by different activating ligands

Abstract

Natural Killer (NK) cells play a pivotal role in immune responses against virally infected or transformed cells. Their activation depends on the stimulation of a broad range of receptors. In the presented work, different aspects of NK cell activity were investigated following co-incubation with murine NIH3T3 cells expressing defined human NK cell ligands to identify the role of individual receptor-ligand interactions. B7H6, MICA, and CD20-bound obinutuzumab engaging NKp30, NKG2D, and CD16, respectively, were revealed to be potent inducers of NK cell activity. Combination with 2B4-ligand CD48 significantly increased degranulation and cytokine secretion in engaged NK cells. Following co-incubation with respective targets, expression levels of multiple receptors were down-regulated in a ligand-specific manner, while CD16 and NKp46 surface levels were reduced based on NK cell activation by any ligand. Co-stimulation via 2B4 in combination with either NKp30, NKG2D, or CD16 significantly enhanced the frequencies of serially degranulating NK cells. Taken together, this systematic investigation provides vital insights into NK cell stimulation that may contribute to the development o