CD1c molecules broadly survey the endocytic system

Abstract

The ability of antigen-presenting cells to sample distinct intracellular compartments is crucial for microbe detection. Major histocompatibility complex class I and class II molecules sample the cytosol or the late endocytic compartment, allowing detection of microbial peptide antigens that arise in distinct intracellular compartments. In contrast, CD1a and CD1b molecules mediate the presentation of lipid and glycolipid antigens and differentially sample early recycling endosomes or late endocytic compartments, respectively, that contain distinct sets of lipid antigens. Here, we show that, unlike the other CD1 isoforms or major histocompatibility complex molecules that each sample restricted only intracellular compartments, CD1c is remarkable in that it distributes broadly throughout the endocytic system and is expressed in both recycling endosomes and late endocytic compartments. Further, in contrast to CD1b, which requires an acidic environment to function, antigen presentation by CD1c was able to overcome dependence on vesicular acidification. Because CD1c is expressed on essential antigen-presenting cells, such as epidermal Langerhans cells (in the absence of CD1b), or on B cells (without CD1a or -b), we suggest that CD1c molecules allow a comprehensive survey for lipid antigens throughout the endocytic system even in the absence of other CD1 isoforms.

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

“…host cell, including early recycling endosomes and lysosomes, where CD1a and CD1b molecules traffic, respectively (9). Further, CD1c molecules are expressed broadly throughout the endocytic system (10). Thus, the intracellular trafficking of phagosome-derived lipid Ags in live mycobacteria-infected cells correlates with the endocytic distribution of CD1 molecules, enabling monitoring of live mycobacterial infection by the CD1 system.…”

“…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).…”

Direct Measurement of Antigen Binding Properties of CD1 Proteins Using Fluorescent Lipid Probes

“…CD1 Proteins-The association with ␤2m in the endoplasmic reticulum is required for assembly of CD1b proteins and for the subsequent transport to the cell surface (35)(36)(37). This observation led us to modify the structure of CD1 proteins by covalently linking ␤2m to the N termini of CD1 via a flexible (G 4 S) 3 linker to create fully assembled secreted CD1 proteins with a single chain CD1 structure (scCD1, Fig.…”

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

“…Subsequently, CD1b molecules are further transported deeply into the endocytic system and reach lysosomes, including the MIIC, as a result of selective binding of the AP-3 complex that is known to interact with certain lysosome-resident proteins, such as lysosome-associated membrane protein-1 (lamp-1) (15). 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).…”