From Lysosomal Storage Diseases to NKT Cell Activation and Back

Abstract

Lysosomal storage diseases (LSDs) are inherited metabolic disorders characterized by the accumulation of different types of substrates in the lysosome. With a multisystemic involvement, LSDs often present a very broad clinical spectrum. In many LSDs, alterations of the immune system were described. Special emphasis was given to Natural Killer T (NKT) cells, a population of lipid-specific T cells that is activated by lipid antigens bound to CD1d (cluster of differentiation 1 d) molecules at the surface of antigen-presenting cells. These cells have important functions in cancer, infection, and autoimmunity and were altered in a variety of LSDs’ mouse models. In some cases, the observed decrease was attributed to defects in either lipid antigen availability, trafficking, processing, or loading in CD1d. Here, we review the current knowledge about NKT cells in the context of LSDs, including the alterations detected, the proposed mechanisms to explain these defects, and the relevance of these findings for disease pathology. Furthermore, the effect of enzyme replacement therapy on NKT cells is also discussed.

Lipid Antigen Presentation by CD1b and CD1d in Lysosomal Storage Disease Patients

“…The frequency of iNKT cells is reduced in different mouse models of LSD (16, 22, 25–30). The same was not observed in NPC (31), Fabry (32), and Gaucher disease (33) patients' blood.…”

“…In addition, the low pH in this compartment induces relaxation of the CD1d structure, facilitating the loading of lipids (21). Indeed, the importance of the lysosome in lipid antigen presentation by mouse CD1d is reinforced by the defects described in mouse models of lysosomal storage diseases (LSDs) (22). LSDs are a group of individually rare inherited metabolic diseases characterized by the accumulation of specific macromolecules in the lysosome, including lipids, usually as a result of a deficiency in a lysosomal enzyme.…”

Mrp1 is involved in lipid presentation and iNKT cell activation by Streptococcus pneumoniae

“…A number of the selected genes have been shown to be related to disease states (using diseases tool—diseases.jensenlab.org) such as lysosomal storage diseases, including Niemann-Pick ( Glb1 and Gal3st ), Fabry ( Psap ), Krabbe disease ( Glb1 and Psap ), Hermansky-Pudlak syndrome ( Tsg101 and Vps16) , some of which have been associated with deficient iNKT cell differentiation as well as defective antigen presentation 27 . Several of the genes identified are reported to be involved in infections, autoimmune and inflammatory diseases, or cancer (Supplementary Table 2 ).…”

“…Because trafficking of CD1d to lysosomes is important for the acquisition of GSL antigens 2 , 13 , 27 , we used confocal microscopy to obtain a quantitative analysis of the localization of CD1d in the J774-CD1d cells at steady state. We used Rab5 as a marker for early endosomes and Lamp1 for late endosomes and lysosomes.…”

Immunometabolic Activation of Invariant Natural Killer T Cells

“…The iNKT cell deficiency in these lysosomal storage disease mouse models suggests that the glycosphingolipid synthetic pathways involved may contain endogenous lipid antigens for iNKT cells. Alternatively, glycosphingolipid accumulation may hinder antigen presentation similarly to acLDL accumulation or cholesterol accumulation following NPC1 deficiency ( 50 ), and possibly NPC2 deficiency ( 52 ), regardless of the glycosphingolipid involved ( 50 , 53 ). The latter model aligns with the lipid raft hypothesis, which proposes that iNKT cell activating lipids may either function as bona fide lipid antigens, or may impact CD1d loading, stabilization or clustering on the cell membrane, and in that way enforce iNKT cell activation ( 50 , 54 – 56 ).…”