Large granular lymphocytes are central cells in the interleukin-2-dependent differentiation pathway of natural killer cells.

Peripheral blood low-density cells were sorted, with respect to their ability to accumulate the lysosomotropic agent mepacrine (Mep), into lysosome-rich (Mep+) and lysosome-poor (Mep-) cell populations. Cells of large granular lymphocyte (LGL) morphology and phenotype were found in the Mep+ but not in the Mep- cell population. The latter cells lacked any natural killer (NK) activity. Cultures of the Mep- cells resulted in the appearance of cells showing K-562 lytic activity, LGL morphology and CD16 and/or Leu-7 positivity. This process was facilitated by the supplementation of the culture with recombinant human interleukin-2 (rIL-2). Mep+ cells retested after 7 days of culture showed a decline in the fraction of granular (LGL and Mep+) cells. This decrease was less pronounced but also seen in rIL-2-supplemented cultures. In spite of the lower number of typical LGL, Mep+ cells cultured with rIL-2 were mostly large but scarcely granular; rIL-2-activated K-562 killing (rIL-2 AK) of originally Mep+ cells was much higher than K-562 lytic activity of these cells at the beginning of the culture, and as compared to rIL-2 AK of Mep- cells. From this finding it is apparent that the most active rIL-2 AK cells originate from low-density granular (Mep+) cells (LGL) and, therefore, we propose to call them 'giant' NK cells. Furthermore, in the presence of rIL-2, LGL differentiate from agranular (Mep-) low-density cells. In view of these data, LGL appear to be resting cells on the differentiation pathway of NK cells.