Separate Pathways for Antigen Presentation by CD1 Molecules

Abstract

The ability to sample relevant intracellular compartments is necessary for effective antigen presentation. To detect peptide antigens, MHC class I and II molecules differentially sample cytosolic and endosomal compartments. CD1 constitutes another lineage of lipid antigen-presenting molecules. We show that CD1b traffics deeply into late endosomal compartments, while CD1a is excluded from these compartments and instead traffics independently in the recycling pathway of the early endocytic system. Further, CD1b but not CD1a antigen presentation is dependent upon vesicular acidification. Since lipids and various bacteria are known to traffic differentially, either penetrating deeply into the endocytic system or following the route of recycling endosomes, these findings elucidate efficient monitoring of distinct components of the endocytic compartment by CD1 lipid antigen-presenting molecules.

CD1 Molecules Efficiently Present Antigen in Immature Dendritic Cells and Traffic Independently of MHC Class II During Dendritic Cell Maturation

“…Unlike CD1b, CD1a molecules are prominently expressed on the surface of immature DCs, with a small fraction localized to early recycling endosomes (18). Thus, labeling of immature DCs with anti-CD1a mAb revealed strong cell surface staining (arrowhead) as well as a few CD1a ϩ intracellular vesicles (Fig.…”

“…CD1c and CD1d also contain similar cytoplasmic tail tyrosine-based sorting motifs, but their failure to bind the AP-3 complex results in their substantial distribution to the early endocytic system, although a fraction of them can reach lysosomes through an undefined pathway (15)(16)(17). Unlike other CD1 molecules, CD1a lacks the cytoplasmic tail tyrosine-based sorting sequence, and, within the endocytic system, is expressed solely in early endosomes of the recycling pathway (18). Together, these observations underscore the capacity of CD1 to broadly survey the endocytic system for sampling lipid Ags that may localize in various endocytic subcompartments (19).…”

Mycobacterium tuberculosisRegulates CD1 Antigen Presentation Pathways through TLR-2

“…It was possible to distinguish between these potential mechanisms by using T cells, which specifically recognize lipid Ags that are made by M. tuberculosis in vivo, but are not produced at detectable levels under the nonpermissive conditions of in vitro growth used to prepare these M. tuberculosis lipid extracts. These Ags were C 80 GMM, a CD1b-presented Ag that is processed in late endosomal compartments (23), and DDM, a CD1a-presented Ag that requires internalization into early endosomal compartments before being recognized (5,25). Monocytes that were pretreated with M. tuberculosis lipid for 3 days and then pulsed with GMM or DDM Ags were found to activate Ag-specific T cells, but untreated monocytes pulsed with Ag did not (Fig.…”

“…For example, myeloid dendritic cells use the mannose receptor (CD206) and Langerhans cells use langerin (CD207) to deliver exogenous lipid Ags to endosomes (17,18), where saposin lipidtransfer proteins and a low pH environment promote binding of lipid Ags to CD1 proteins (19 -22). Such endosomal loading pathways are necessary for efficient T cell activation by most or all known bacterial lipid Ags, including mycolic acid, lipoarabinomannan (LAM), glucose monomycolate (GMM), mannosyl phosphomycoketides, and didehydroxymycobactins (DDM) (1,4,(23)(24)(25). A general implication of the discovery of endosomal pathways for loading lipid Ags onto CD1 proteins is that APCs can actively control which Ags are displayed to T cells by controlling which lipids are taken up into endosomal compartments (26).…”

Cutting Edge: Major CD8 T Cell Response to Live Bacillus Calmette-Guérin Is Mediated by CD1 Molecules

“…Given that DCs are the most efficient APCs in the immune system and that, besides macrophages, DCs represent another important reservoir for mycobacteria (7), group 1 CD1-dependent activation of CD8 ϩ T cells may occur during the course of mycobacterial infection (8). In addition, CD1 molecules are expressed intracellularly in endocytic subcompartments where lipid Ags derived from phagocytosed mycobacteria are known to traffic (9,10), raising the possibility that CD1 molecules may be situated to efficiently monitor infection with live mycobacteria. Indeed, group 1 CD1-restricted CD8 ϩ T cell lines were isolated from healthy subjects as well as patients with mycobacterial infection, and their outstanding ability to recognize mycobacteria-infected cells and kill the intracellular organisms has been noted (11).…”