Pathways for Cytolysis

Griffiths, G M, Argon, Y, Griffiths, G. M., Argon, Y.

Lytic granules are specialized secretory organelles which appear after activation of CTLs and NK cells. The lytic granules contain a series of proteins that mediate target cell destruction after secretion from the cell. In addition, these organelles serve as the lysosomes of these lymphocytes. At the EM level three types of granules with distinct regions are distinguished. Intriguingly, lytic and lysosomal proteins are localized in distinct regions. This is particularly interesting because lysosomal and lytic proteins can use the same sorting mechanisms to be targeted to this compartment. We favor the idea that a combination of sorting mechanisms result in this final segregation: the MPR receptor sorts both lysosomal proteins and granzymes from the Golgi complex, but a second event, such as selective aggregation with proteoglycans, then results in the segregation of lytic and lysosomal proteins in the granule. Lytic granules provide a way to store and simultaneously secrete the lytic proteins in a highly specific fashion. The granules are able to move along microtubules using a kinesin-like motor, and thus can cluster at the site of membrane contact with a target cell. Once polarized, the granules exocytose their contents, using a molecular machinery that is as yet poorly defined. Understanding the machinery involved in both functions of the lytic granules will provide ways to control the action of cytotoxic lymphocytes, ultimately in clinical situations.