Cytolytic granules are formed from components of late endosomes and lysosomes. Once formed, there are multiple steps in the exocytosis of cytolytic granules from cytotoxic cells and their delivery to target cells. The importance of the cytolytic pathway in immune regulation is highlighted by inherited defects that impair key steps in either the formation or the exocytosis of cytolytic granules (Fig. 13.9). These result in a severe and often fatal condition, known as hemophagocytic lymphohistiocytic (HLH) syndrome, which manifests as uncontrolled activation and expansion of CD8 T lymphocytes and macrophages that infiltrate multiple organs, causing tissue necrosis and organ failure. The hyperactive immune response is thought to reflect the inability of cytotoxic cells to destroy infected targets, and possibly themselves, following an initiating viral infection, particularly by a herpes family virus such as Epstein–Barr virus (EBV). In this regard it is notable that despite the impaired release of cytolytic granules, the release of IFNγ by CTLs and NK cells of patients with this disorder is not typically impaired, which contributes to the heightened activity of macrophages and associated inflammatory disorder caused by an increased release of proinflammatory cytokines such TNF, IL6, and macrophage colonystimulating factor (MCSF). The activated macrophages phagocytose blood cells, including erythrocytes and leukocytes, which gives the syndrome its name.
There are multiple autosomal recessive variants of HLH, also referred to as familial hemophagocytic lymphohistiocytosis (FHL), that are distinguished by the protein in the cytolytic pathway that is affected (see Fig. 13.9). Examples include inherited deficiencies of the cytolytic granule protein perforin, which is required for pore formation in the target cell (and when defective is associated with the syndrome FHL2); of the priming protein, Munc134 (FHL3); of syntaxin 11 (FHL4), a member of the SNARE family of proteins that mediate membrane fusion; and of Munc182 (FHL5), a protein involved in the reorganization of SNARE proteins to activate the fusion process. Because components of the biogenesis and exocytosis of cytolytic granules are shared with other secretory vesicles, such as lysosomes, additional immune defects can occur in affected individuals, as can nonimmune defects. In particular, a subset of the immunodeficiencies that affect cytolytic granule function are also characterized by partial loss of skin pigmentation. This is due to defects in vesicular transport proteins that are also required for the formation or exocytosis of melanosomes, organelles that store the skin pigment melanin in melanocytes. Examples of these immunodeficiencies include Chediak–Higashi syndrome, caused by mutations in a protein, CHS1, which regulates lysosomal trafficking, and Griscelli syndrome, caused by mutations in a small GTPase, RAB27a (see Fig. 13.9), which is integral to the tethering of certain vesicles, including cytolytic granules, to cytoskeletal structures to enable their intracellular trafficking.