Niemann-Pick disease C1 (NP-C1) is a rare lysosomal storage illness caused by mutations in the NPC1 endolysosomal cholesterol transporter. Despite having prominent neurological symptoms, NP-C1 is also similar to long-term congenital immunodeficiencies caused by cytotoxic T lymphocyte (CTL) effector function impairment. CTLs kill their targets by exocytosing the contents of lysosome-like secretory cytotoxic granules (CGs), which store and eventually release the critical pore-forming protein perforin as well as proapoptotic serine proteases, granzymes, into the synapse established between the CTL and target cell. NPC1 loss increases CG lipid load, affects autophagic flux through halted trafficking of the transcription factor EB (TFEB), and significantly lowers CTL cytotoxicity. 

Using a combination of immunological and cell biological approaches, researchers for a study discovered that cytotoxic deficiency is caused by a defect in perforin pore formation. They found that patients with NP-C1 had variable degrees of CTL function abnormalities, with the most severe losses of function linked with the most florid and/or earliest illness presentations. Surprisingly, by increasing lipid clearance with therapeutic 2-hydroxypropyl—cyclodextrin, perforin function, and CTL cytotoxicity were restored in vitro; however, restoration of autophagy by TFEB overexpression was unsuccessful. Overall, the findings showed that NPC1 deficiency impairs CTL (but not natural killer cell) cytotoxicity, which may predispose patients with NP-C1 to atypical infections and reduced immunological surveillance in general.