Lysosomal Lipases PLRP2 and LPLA2 Process Mycobacterial Multi-acylated Lipids and Generate T Cell Stimulatory Antigens.
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.
Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse 31077, France. Electronic address: martine.gilleron@ipbs.fr.
Martine
M
Gilleron
Experimental Immunology, Department of Biomedicine, University Hospital and University of Basel, Basel 4031, Switzerland.
Marco
M
Lepore
Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse 31077, France.
Emilie
E
Layre
Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse 31077, France.
Diane
D
Cala-De Paepe
Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse 31077, France.
Naila
N
Mebarek
Nephrology Division, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
James A
JA
Shayman
CNRS, Aix Marseille Université, UMR7282 Enzymology at Interfaces and Physiology of Lipolysis, Marseille Cedex 20 13402, France.
Stéphane
S
Canaan
Experimental Immunology, Department of Biomedicine, University Hospital and University of Basel, Basel 4031, Switzerland; Singapore Immunology Network, Agency for Science, Technology and Research, Singapore 138648, Singapore.
Lucia
L
Mori
CNRS, Aix Marseille Université, UMR7282 Enzymology at Interfaces and Physiology of Lipolysis, Marseille Cedex 20 13402, France.
Frédéric
F
Carrière
Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse 31077, France.
Germain
G
Puzo
Experimental Immunology, Department of Biomedicine, University Hospital and University of Basel, Basel 4031, Switzerland; Singapore Immunology Network, Agency for Science, Technology and Research, Singapore 138648, Singapore. Electronic address: gennaro.delibero@unibas.ch.
Gennaro
G
De Libero
D000215:Acylation; D017951:Antigen Presentation / Q000235:genetics; D000941:Antigens / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D008049:Lipase / Q000235:genetics / Q000378:metabolism*; D008055:Lipids; D008213:Lymphocyte Activation; D008247:Lysosomes / Q000201:enzymology*; D009161:Mycobacterium / Q000378:metabolism*; D054467:Phospholipases A2 / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
D000941:Antigens; D008055:Lipids; D008049:Lipase; C075988:pancreatic lipase related protein 2; D054467:Phospholipases A2