Niemann-Pick disease type C1 (NP-C1) is a rare lysosomal storage disorder resulting from mutations in an endolysosomal
cholesterol transporter, NPC1. Despite typically presenting with pronounced
neurological manifestations, NP-C1 also resembles long-term congenital immunodeficiencies that arise from impairment of cytotoxic T lymphocyte (CTL) effector function. CTLs kill their targets through exocytosis of the contents of lysosome-like secretory cytotoxic granules (CGs) that store and ultimately release the essential pore-forming
protein perforin and proapoptotic
serine proteases,
granzymes, into the synapse formed between the CTL and target cell. We discovered that NPC1 deficiency increases CG
lipid burden, impairs autophagic flux through stalled trafficking of the
transcription factor EB (TFEB), and dramatically reduces CTL cytotoxicity. Using a variety of immunological and cell biological techniques, we found that the cytotoxic defect arises specifically from impaired
perforin pore formation. We demonstrated defects of CTL function of varying severity in patients with NP-C1, with the greatest losses of function associated with the most florid and/or earliest disease presentations. Remarkably,
perforin function and CTL cytotoxicity were restored in vitro by promoting
lipid clearance with therapeutic 2-hydroxypropyl-β-
cyclodextrin; however, restoration of autophagy through TFEB overexpression was ineffective. Overall, our study revealed that NPC1 deficiency has a deleterious impact on CTL (but not natural killer cell) cytotoxicity that, in the long term, may predispose patients with NP-C1 to atypical
infections and impaired immune surveillance more generally.