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Lysosomal Lipases PLRP2 and LPLA2 Process Mycobacterial Multi-acylated Lipids and Generate T Cell Stimulatory Antigens.

Cell Chem Biol. 2016 Sep 22;23(9):1147-1156
Martine Gilleron 1 , Marco Lepore 2 , Emilie Layre 3 , Diane Cala-De Paepe 3 , Naila Mebarek 3 , James A Shayman 4 , Stéphane Canaan 5 , Lucia Mori 6 , Frédéric Carrière 5 , Germain Puzo 3 , Gennaro De Libero 7
Martine Gilleron 1 , Marco Lepore 2 , Emilie Layre 3 , Diane Cala-De Paepe 3 , Naila Mebarek 3 , James A Shayman 4 , Stéphane Canaan 5 , Lucia Mori 6 , Frédéric Carrière 5 , Germain Puzo 3 , Gennaro De Libero 7
+ et al

[No authors listed]

Author information
  • 1 Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse 31077, France. Electronic address: martine.gilleron@ipbs.fr.
  • 2 Experimental Immunology, Department of Biomedicine, University Hospital and University of Basel, Basel 4031, Switzerland.
  • 3 Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse 31077, France.
  • 4 Nephrology Division, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • 5 CNRS, Aix Marseille Université, UMR7282 Enzymology at Interfaces and Physiology of Lipolysis, Marseille Cedex 20 13402, France.
  • 6 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.
  • 7 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.

摘要

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.

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