CD1c bypasses lysosomes to present a lipopeptide antigen with 12 amino acids

Abstract

The recent discovery of dideoxymycobactin (DDM) as a ligand for CD1a demonstrates how a nonribosomal lipopeptide antigen is presented to T cells. DDM contains an unusual acylation motif and a peptide sequence present only in mycobacteria, but its discovery raises the possibility that ribosomally produced viral or mammalian proteins that commonly undergo lipidation might also function as antigens. To test this, we measured T cell responses to synthetic acylpeptides that mimic lipoproteins produced by cells and viruses. CD1c presented an N-acyl glycine dodecamer peptide (lipo-12) to human T cells, and the response was specific for the acyl linkage as well as the peptide length and sequence. Thus, CD1c represents the second member of the CD1 family to present lipopeptides. lipo-12 was efficiently recognized when presented by intact cells, and unlike DDM, it was inactivated by proteases and augmented by protease inhibitors. Although lysosomes often promote antigen presentation by CD1, rerouting CD1c to lysosomes by mutating CD1 tail sequences caused reduction in lipo-12 presentation. Thus, although certain antigens require antigen processing in lysosomes, others are destroyed there, providing a hypothesis for the evolutionary conservation of large CD1 families containing isoforms that survey early endosomal pathways.

Synthesis of Dideoxymycobactin Antigens Presented by CD1a Reveals T Cell Fine Specificity for Natural Lipopeptide Structures

“…The titer and extent of inhibition was similar to that of the known CD1a-presented ligand, sulfatide, and is similar to the recently observed effects of CD1c-presented ligands (supplemental Fig. S10, B and C) (49).…”

Antibody Response to Polyhistidine-Tagged Peptide and Protein Antigens Attached to Liposomes via Lipid-Linked Nitrilotriacetic Acid in Mice

“…This effect may be antigen specific, since N-MPR required liposome attachment, via either an NTA linkage or a covalent conjugation, to elicit an antibody response. The greater serum antibody titers induced by covalent antigen attachment could be explained by a benefit in antigen processing downstream of particulate association and internalization or by stimulation of innate pattern recognition receptors (38,46). Indeed, we have found that the structure of the lipid anchor dramatically affected the serum IgG response to liposomal N-MPR lipopeptides despite complete retention of all antigens in the liposome formulation (47).…”

Golgi-to-phagosome transport of acid sphingomyelinase and prosaposin is mediated by sortilin

“…An alternative pathway to the phagosome mediated by sortilin could represent another level of regulation during the development of the immune response. For example, some lipid antigens are loaded into CD1c molecules that bypass the lysosomal compartment (Van Rhijn et al, 2009).…”