Lipid Antigen Presentation by CD1
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Lipid Antigen Presentation by CD1

The CD1 (Thymocyte Antigen CD1) antigen presentation system presents lipid and glycolipid antigens to effector T-Cells, which have diverse roles in Antimicrobial responses, Antitumor immunity and in regulating the balance between Tolerance and Autoimmunity. CD1, a conserved family of MHC (Major Histocompatibility Complex)-like glycoproteins in mammals, specializes in capturing lipid rather than peptide antigen for presentation to T-lymphocytes (Ref.1). The CD1 family consists of five isoforms of non-polymorphic lipid antigen-presenting molecules, which are classified into two groups: Group-I (CD1A, CD1B, CD1C, and CD1E) and Group-II (CD1D), based on similarities between nucleotide and amino acid sequences. Topologically, they resemble the classical peptide antigen-presenting MHC molecules except that the large, exclusively nonpolar and hydrophobic, antigen-binding groove of CD1 has evolved to present a variety of cellular and pathogen-derived lipids and glycolipids to specific T lymphocytes. Most mammals express both Group-I and Group-II CD1 proteins (human), but some express only Group-II (mice and rats) proteins (Ref.2 & 3). Group-I CD1 proteins present self and bacterial lipids to specific T-Cells, whereas CD1D displays self-lipids for an appraisal by a specialized subset of T-lymphocytes called NKT (Natural Killer T-Cells) Cells. CD1 proteins accomplish their Antigen-presenting function by binding the alkyl chains of the lipid Antigens within a deep, hydrophobic groove on the membrane distal surface of CD1, making the hydrophilic elements of the Antigen available for contact with the variable regions of Antigen-specific TCRs (T-Cell Receptors) of CD1-restricted T-Cells (Ref.4). CD1-restricted T-Cells carry out effector, helper, and adjuvant-like functions and interact with other cell types including Macrophages, Dendritic cells, NK cells, T-Cells, and B-Cells, thereby contributing to both Innate and Adaptive immune responses. Group-I molecules (except CD1E whose function is yet to be found out) present Microbial Fatty Acids, Glycolipids, Phospholipids and Lipopeptide Antigens. CD1D (Group-II) molecules mainly present self-lipid antigens, including Sphingolipids and Diacylglycerols; and Alpha-Ceramides are used pharmacologically to examine the function of CD1D-restricted T-Cells. CD1D binds self-lipids by the same mechanism that Group-1 CD1 molecules bind exogenous lipids (Ref.3 & 5).

The intracellular trafficking of CD1 proteins is central to their ability to deliver the foreign antigens to the cell surface where they can be recognized by T-Cells. The trafficking of CD1 molecules and lipid antigens facilitates their intersection and binding in specific intracellular compartments. The CD1 proteins acquire immunocompetence in the ER (Endoplasmic Reticulum) of Antigen Presenting Cells (Ref.1). These proteins contain three extracellular domains (Alpha1, Alpha2 and Alpha3) and that are known as HCs (Heavy Chains) because of their homology to MHC-I (MHC Class-I) HC. All CD1 protein sequences contain a leader peptide, which signals co-translational insertion of the HC into the ER membrane, such that the Alpha1 and Alpha2 domains, which form the antigen-binding pocket of CD1, and the Alpha3 domain are in the lumen of the ER. This leaves the short tails of the CD1 HCs, which are composed generally of 6-10 amino acids, protruding into the cytoplasmic compartment. Folding of the CD1 HCs brings the hydrophobic amino acids of the Alpha1 and Alpha2 domains into close proximity, so that they form a nearly continuous hydrophobic surface that constitutes the inner surface of the CD1 antigen-binding groove. Newly synthesized CD1 HCs are translocated into the ER where these associate rapidly with the protein-folding chaperones Calnexin and Calreticulin. This complex, in turn, recruits Beta2M resulting in disassociation of CD1 from the complex, its subsequent association with Beta2M (Ref.2, 4 & 8).

The CD1-Beta2M association is necessary for the normal cell-surface expression of CD1 proteins and for the regulation of their egress from the ER to the plasma membrane along the Secretory Route, through the TGN (Trans-Golgi Network) (Ref.6 & 7). Self-lipids are loaded onto CD1-Beta2M complexes during assembly in the ER to occupy the hydrophobic antigen-binding groove during traffic through the secretory and endocytic system. Loading of self-lipids to the antigen-binding grooves of CD1 molecules in the ER has a physiological role in blocking the CD1 groove for antigen binding, analogous to the known function of CLIP (Class-II Ii (Invariant Chain) Peptide) in binding to MHC-II (MHC Class-II) molecules. Ubiquitous self-ligands, such as PI (Phosphatidylinositol), are bound to CD1 molecules at early stages in the secretory pathway, and function as non-antigenic lipid chaperones that protect the integrity of the antigen-binding CD1 groove before the CD1 molecules encounter more antigenic lipids during trafficking through later stages of the secretory or endocytic compartments (Ref.4 & 8).  Following assembly in the ER, the CD1-Beta2M -Selflipid complexes are transported to the plasma membrane. From the surface, 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 or microbial lipids present in endosomal compartments (Ref.2 & 7). Three successive endosomal compartments: SE (Sorting Endosome), EE (Early Endosome), and LE (Late Endosome) are generally traversed by the CD1 Proteins during the endocytic pathway. The endosomal compartments are speculated to contain enzymes capable of trimming the polysaccharide or the fatty-acid components of glycolipids. AP (Adaptor-Protein) complexes control the CD1 trafficking. Access to the endocytic pathway is regulated by a tyrosine-based motif in the cytoplasmic tail of CD1 proteins. The cytoplasmic tails of each of these CD1 isoforms interact differently with AP complexes that control their intracellular trafficking and their ability to select and activate CD1-restricted T-Cells. AP complexes: AP2 (Adaptor Protein-2) and AP3 (Adaptor Protein-3) control intracellular sorting by binding amino-acid motifs in the cytoplasmic tails of certain transmembrane proteins, leading to their packaging into transport vesicles. A sequence of four amino acids (YXXZ; where Y is tyrosine, X is any amino acid and Z is a bulky hydrophobic residue) mediates binding to the AP. Both tyrosine- and leucine-based cytoplasmic tail motifs are involved in control of the intracellular sorting of CD1 proteins (Ref.6 & 8).

Each of the human CD1 proteins takes a different route through the endocytic compartments before finally arriving at the cell surface, where these proteins present glycolipid antigens to T-Cells. 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 ARF6 (ADP-Ribosylation Factor-6)-dependent manner. CD1A has a particularly short cytoplasmic tail that lacks the YXXZ motif that could mediate binding to AP and sorting into specialized endosomal compartments and is largely excluded from lysosomes (Ref.6). The functions of CD1A include the activation of autoreactive T-Cells, a process that includes the presentation of self-antigens. In addition, CD1A 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. It is then sorted to LE and directed to Lysosomes by binding the AP3. CD1B acquires distinct self- or foreign lipid antigens in the LEs. It presents three classes of antigens: Mycolates (free Mycolic Acid and Glucose Monomycolate), Diacylglycerols (Phosphatidylinositol Mannoside, Lipoarabinomannan, and Phosphatidylinositol) and Sphingolipids. The YXXZ motif of CD1B is unique among the human CD1 isoforms in its ability to bind AP3 (Ref.7 & 8). CD1C broadly traffics in both early recycling endosomes as well as in LE and Lysosomes. CD1C-restricted T cells recognize Mycobacterial Mannosyl-Beta-1-Phosphoisoprenoid, a glycophospholipid with only a single short lipid tail (Ref.2 & 5). CD1D traffics mainly in EE and LEs and partially localizes in Lysosomes. The cytoplasmic tails of CD1C and CD1D contain tyrosine-based YXXZ motifs, which bind to AP2 complexes at the cell surface. This interaction mediates sorting and delivery to Endosomes (Ref.3). The tails of CD1D proteins also contain a functional modified dileucine motif, which acts as a second signal to mediate its sorting to late endosomes. In addition, a fraction of CD1D proteins (truncated form of CD1D which lacks its cytoplasmic YXXZ internalization motif) is transported to late endosomal/lysosomal compartments in the presence of MHC-II molecules and are diverted to LEs or MIIC (MHC-II Compartments), before being presented to the T-Cells at the cell surface. This diversion to MIIC is also evident in case of CD1B proteins, but it is dependent on the tyrosine-based motif in its own cytoplasmic tail (Ref.8 & 9).

CD1-restricted T-Cells can be stimulated by exposure to CD1+ Antigen-Presenting Cells in the absence of foreign antigens, resulting in their activation as measured by proliferation, cytokine secretion, or cytolysis. These T-Cells function in Infectious, Neoplastic, or Autoimmune diseases and are based on the premise that CD1-restricted T-Cell responses are initiated by alterations in cellular glycolipid content. The principles and mechanisms of the newly discovered immune strategy of lipid antigen presentation differ markedly from those governing classical MHC-peptide presentation. These mechanisms can be exploited for studying the evolution of host-pathogen relations and for the design of new lipid-based microbial vaccines and adjuvants (Ref.8, 9 & 10).