Lysosomal Lipases PLRP2 and LPLA2 Process Mycobacterial Multi-acylated Lipids and Generate T Cell Stimulatory Antigens. Issue 9 (22nd September 2016)

• Record Type: Journal Article
• Authors: Gilleron, Martine; Lepore, Marco; Layre, Emilie; Cala-De Paepe, Diane; Mebarek, Naila; Shayman, James A.; Canaan, Stéphane; Mori, Lucia; Carrière, Frédéric; Puzo, Germain; De Libero, Gennaro
• Is Part Of: Cell chemical biology. Volume 23:Issue 9(2016)
• Page Start: 1147
• Page End: 1156
• Publication Date: 2016-09-22
• Subjects: Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2016.07.021
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: Complex antigens require processing within antigen-presenting cells (APCs) to form T cell stimulatory complexes with CD1 antigen-presenting molecules. It remains unknown whether lipids with multi-acylated moieties also necessitate digestion by lipases to become capable of binding CD1 molecules and stimulate T cells. Here, we show that the mycobacterial tetra-acylated glycolipid antigens phosphatidyl- myo- inositol mannosides (PIM) are digested to di-acylated forms by pancreatic lipase-related protein 2 (PLRP2) and lysosomal phospholipase A2 (LPLA2) within APCs. Recombinant PLRP2 and LPLA2 removed the sn1- and sn2-bound fatty acids from the PIM glycerol moiety, as revealed by mass spectrometry and nuclear magnetic resonance studies. PLRP2 or LPLA2 gene silencing in APCs abolished PIM presentation to T cells, thus revealing an essential role of both lipases in vivo. These findings show that endosomal lipases participate in lipid antigen presentation by processing lipid antigens and have a role in T cell immunity against mycobacteria. Graphical Abstract: Highlights: CD1b-restricted T cells recognize unusual di-acylated species of mycobacterial PIM PLRP2 and LPLA2 lysosomal lipases digest tetra- into di-acylated PIM in vitro PLRP2 and LPLA2 siRNA in APCs abrogate presentation of tetra-acylated PIM to T cells PIM presentation to CD1b-restricted T cells requires both PLRP2 and LPLA2 Abstract : Complex antigenic glycolipids require processing to form T cell stimulatory complexes with CD1 proteins. Gilleron et al. demonstrate that, in addition to the glycosidic part, the lipid moiety of multi-acylated mycobacterial glycolipids also needs to be processed by lysosomal lipases.