Lytic granule polarization, rather than degranulation, is the preferred target of inhibitory receptors in NK cells.

Natural cytotoxicity is achieved by polarized release of perforin and granzymes at the NK cell-target cell immunological synapse. Signals for granule polarization and degranulation can be uncoupled in NK cells, which raises the question of their respective sensitivity to inhibitory receptors. Expression of either HLA-C or HLA-E on the human cell line 721.221 blocked granule polarization, degranulation, and CD16-dependent MIP-1α secretion by NK cell clones that expressed inhibitory receptors of matching HLA specificity. To test inhibition of signals for polarization and degranulation separately, Drosophila S2 cells expressing ICAM-1 with either HLA-C or HLA-E were used. CD16-dependent degranulation and MIP-1α secretion were not fully inhibited, suggesting that other receptor-ligand interactions, which occur with 721.221 cells, contribute to inhibition. In contrast, HLA-C or HLA-E on S2 cells coexpressing ICAM-1 or ULBP1 were sufficient to block granule polarization induced by either LFA-1 or NKG2D, even during concomitant CD16-dependent degranulation. Similarly, expression of a ligand for NKR-P1A on S2 cells inhibited granule polarization but not CD16-induced degranulation. Therefore, granule polarization, rather than degranulation, is the preferred target of inhibitory receptors in NK cells.