How the Immune System Handles Lipid Antigens

Researchers have identified a mechanism that may explain how the immune system responds to lipid antigens such as those displayed by the tuberculosis bacterium.

Investigators at the Scripps Research Institute (La Jolla, CA, USA) genetically engineered a line of mice lacking the gene that encodes for the protein prosaposin. Prosaposin normally exists in two forms: a 65 kDa form targeted to lysosomes and an unprocessed 70 kDa form secreted extracellularly. Prosaposin also exists as an integral membrane protein not destined for lysosomal entry and exists uncleaved in many biologic fluids such as seminal plasma, human milk, and cerebrospinal fluid, where it appears to have a different function. The function of lysosomal saposins is to either solubilize certain membrane glycolipids or to form complexes with lysosomal enzymes and/or their glycolipid substrate to facilitate their hydrolysis. The function of the secreted form is still unclear. It has been suggested that it may function as a glycolipid transfer protein.

Results of the study, which were published December 18, 2003, in the online edition of Science, showed that mice lacking prosaposin had specific defects in CD1d-mediated antigen presentation and lacked V-alpha 14 natural killer T cells. Without prosaposin, the CD1 proteins never became loaded with lipid, and therefore NK T cells could not be selected in the thymus of the modified mice. In vitro, saposins extracted monomeric lipids from membranes and from CD1, thereby promoting the loading as well as the editing of lipids on CD1.

"These NK T cells are the master keys for the regulation of the immune system,” explained senior author Dr. Luc Teyton, an associate professor in the immunology department of the Scripps Research Institute. "This is the first time someone has shown how the immune system and lipid metabolism merge.”



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