Abstract
Lipids are important antigens that induce T cell-mediated specific immune responses. They are presented to T lymphocytes by a specific class of MHC-I like proteins, termed CD1. The majority of the described CD1-presented mycobacterial antigens are presented by the CD1b isoform. We previously demonstrated that the stimulation of CD1b-restricted T cells by the hexamannosylated phosphatidyl-myo-inositol (PIM(6)), a family of mycobacterial antigens, requires a prior partial digestion of the antigen oligomannoside moiety by α-mannosidase and that CD1e is an accessory protein absolutely required for the generation of the lipid immunogenic form. Here, we show that CD1e behaves as a lipid transfer protein influencing lipid immunoediting and membrane transfer of PIM lipids. CD1e selectively assists the α-mannosidase-dependent digestion of PIM(6) species according to their degree of acylation. Moreover, CD1e transfers only diacylated PIM from donor to acceptor liposomes and also from membranes to CD1b. This study provides new insight into the molecular mechanisms by which CD1e contributes to lipid immunoediting and CD1-restricted presentation to T cells.
Highlights
To become antigenic, mycobacterial hexamannosylated phosphatidyl-myo-inositol (PIM6) undergo CD1eassisted ␣-mannosidase processing
CD1e Assists Mannosidase in Processing of Specific Acyl Forms of PIM—Previously, we showed that CD1e acts as an accessory protein to assist ␣-mannosidase-mediated processing of PIM6 into PIM2, which is required for CD1b-restricted T cells activation [7]
The stimulation of CD1b-restricted T cells by PIM6, a family of mycobacterial antigens, requires a partial digestion of the PIM oligomannoside moiety by an ␣-mannosidase and CD1e is absolutely required for antigen processing and T cell stimulation [7]
Summary
Mycobacterial hexamannosylated phosphatidyl-myo-inositol (PIM6) undergo CD1eassisted ␣-mannosidase processing. We previously demonstrated that the stimulation of CD1b-restricted T cells by the hexamannosylated phosphatidyl-myo-inositol (PIM6), a family of mycobacterial antigens, requires a prior partial digestion of the antigen oligomannoside moiety by ␣-mannosidase and that CD1e is an accessory protein absolutely required for the generation of the lipid immunogenic form. Five activator proteins of sphingolipid catabolism have been described, saposin-A to saposin-D (Sap-A to Sap-D) and the GM2 activator protein (GM2AP) These are non-enzymatic cofactors involved in the degradation of sphingolipids by lysosomal hydrolases [10], assisting membrane-inserted substrate digestion. In the absence of CD1e, PIM6 are digested to phosphatidyl-myo-inositol trimannosides (PIM3), which are not able to stimulate the PIM-specific T cells Both the multiple effects of CD1e on antigen presentation [8] and its structural characteristics [9] suggest that CD1e might have evolved to mediate lipid exchange/editing processes. This finding is in accordance with the fact that only liposome-inserted diacylated PIM6 species can be digested by ␣-mannosidase to generate PIM2
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