B cells need mannose 6-phosphate to proliferate, differentiate, and present antigens, Otomo et al. show.
Immune cells slice up antigens in lysosomes and attach the fragments to MHC II complexes, which then display them on the cell surface. To ensure that they can cut up the antigens, cells steer newly made proteases to the organelles by tagging them with mannose 6-phosphate molecules. In the rare disease mucolipidosis II, patients can’t synthesize mannose 6-phosphate, and their lysosomes fill up with undigested molecular junk known as storage material.
To find out how loss of mannose 6-phosphate affects different kinds of immune cells, Otomo et al. used knock-in mice that mimic symptoms of mucolipidosis II patients. The animals’ B cells were abnormal. Their lysosomes bulged with storage material, and they were poor at dismembering antigens and breaking down CD74, a protein that prevents the MHC II complex from binding antigen fragments.
B cells show off antigenic peptides to CD4+ T cells, and the interaction spurs B cells to mature, proliferate, and differentiate into antibody-making plasma cells. All three processes were impaired in B cells from the mutant mice. The researchers found that B cells from mucolipidosis II patients were also defective and produced fewer IgG, IgM, and IgA antibodies than normal.
However, other types of immune cells in the mice weren’t as severely affected. For example, dendritic cells broke down antigens normally and didn’t accumulate storage material, although their ability to present antigens to T cells was below par. Thus, B cells are more dependent on mannose 6-phosphate than are other immune cells. The enzymes in these other cells presumably reach the lysosome through mannose 6-phosphate–independent pathways.
Text by Mitch Leslie