Lipid Antigen Presentation by CD1

CD1, a conserved family of MHC-like glycoproteins specializes in capturing lipid rather than peptide antigen for presentation to T-lymphocytes. The CD1 family consists of five isoforms which are classified into two groups: Group-I (CD1A, CD1B, CD1C, and CD1E) and Group-II (CD1D). Group-I CD1 proteins present self and bacterial lipids to specific T-cells whereas CD1D displays self lipids including sphingolipids and diacylglycerols. CD1-restricted T-cells contribute to both innate and adaptive immune responses. Group-I molecules present microbial fatty acids, glycolipids, phospholipids and lipopeptide antigens.All CD1 protein sequences contain a leader peptide, which signals co-translational insertion of the heavy chain into the ER membrane, such that the α1 and α2 domains, which form the antigen-binding pocket of CD1, and the α3 domain are in the lumen of the ER. This leaves the short tails of the CD1 heavy chains protruding into the cytoplasmic compartment. Newly synthesized CD1 heavy chains are translocated into the ER where these associate rapidly with the protein-folding chaperones Calnexin and Calreticulin. This complex in turn recruits β2M resulting in dissociation of CD1 from the complex and its subsequent association with β2M.Self lipids are loaded onto CD1-β2M complexes during assembly in the ER to occupy the hydrophobic antigen binding groove during traffic through the secretory and endocytic system. Following assembly in the ER, the CD1-β2M-self lipid complexes are transported to the plasma membrane. Then CD1 is re-internalized and each isoform differentially traffics through the endocytic system where it is able to exchange previously loaded self lipids with the antigenic self lipids present in endosomal compartments. Three successive endosomal compartments: Sorting Endosome (SE), Early Endosome (EE) and Late Endosome (LE) are generally traversed by the CD1 proteins during the endocytic pathway. AP complexes control the CD1 trafficking. AP complexes control intracellular sorting by binding amino acid motifs in the cytoplasmic tails of certain transmembrane proteins leading to their packaging into transport vesicles.After export by the secretory pathway, CD1A is found mainly at the cell surface. It is then sorted into SEs, acquires distinct self or foreign lipid antigens and traffics back to the plasma membrane in an AFR6 dependent manner. CD1A activates autoreactive T-cells, a process that includes the presentation of self antigens. CD1A also presents exogenously acquired polar lipids from mycobacterial cell walls for recognition by antigen specific T-cells. After reaching the plasma membrane through the secretory pathway, CD1B molecules interact with AP2 and follow a pathway of internalization. They are then sorted to LE and directed to lysosomes by binding the AP3. CD1B acquires distinct self or foreign lipid antigens in the LE. It presents three classes of antigens: mycolates, diacylglycerols and sphingolipids. CD1C broadly traffics in both early recycling endosomes as well as in LE and lysosomes. CD1C restricted T cells recognize mycobacterial mannosyl-β-1-phosphoisoprenoid. CD1D traffics mainly in EE and LE and partially localizes in lysosomes. The cytoplasmic tails of CD1C and CD1D bind to AP2 complexes at the cell surface which then mediates sorting and delivery to endosomes. A fraction of CD1D proteins is transported to late endosomal/lysosomal compartments in the presence of MHC-II molecules and are diverted to LE or MHC-II compartments before being presented to T-cells at the cell surface.The mechanism of the newly discovered immune strategy of lipid antigen presentation differs from those governing classical MHC-peptide presentation. This can be exploited to study the evolution of host-pathogen relations and for the design of new lipid based microbial vaccines and adjuvants.