CD1D - CD1d molecule |Elisa - Clia - Antibody - Protein

Background

CD1D is a key member of the CD1 family of glycoproteins, which are specialized antigen-presenting molecules. CD1 proteins are distinct from classical major histocompatibility complex (MHC) class I and II molecules in that they present lipid and glycolipid antigens, rather than peptide antigens, to T cells. CD1D is unique within the CD1 family because of its specialized role in presenting lipid antigens to natural killer T (NKT) cells, particularly the invariant NKT (iNKT) cells, which express a semi-invariant T cell receptor (TCR). This interaction is essential for initiating rapid immune responses against a variety of pathogens, as well as in immune regulation.

CD1D is expressed predominantly on antigen-presenting cells (APCs), such as dendritic cells, macrophages, and B cells, but is also found on certain epithelial cells. Through its interaction with NKT cells, CD1D mediates a range of immune responses, including the production of cytokines that regulate the function of other immune cells, such as dendritic cells, natural killer (NK) cells, and conventional T cells. This makes CD1D important not only for pathogen defense but also for the regulation of inflammation, tolerance, and tumor immunity.

The CD1D-NKT cell axis has gained significant interest in the field of immunology due to its dual role in promoting both immune activation and immune regulation. It is crucial in the defense against microbial pathogens, particularly those that have lipid-containing cell walls like mycobacteria, but is also involved in maintaining immune tolerance and preventing excessive inflammatory responses.

Protein Structure

The CD1D molecule is structurally similar to MHC class I molecules, with certain adaptations that enable it to bind and present lipid antigens. It consists of two main components: a heavy chain (~48 kDa) and a non-covalently associated β2-microglobulin (β2m) light chain (~12 kDa), similar to other CD1 family members. However, the structural features that allow CD1D to present lipid rather than peptide antigens are unique.

Primary Structure:

The CD1D heavy chain contains three extracellular domains (α1, α2, and α3), a transmembrane domain, and a short cytoplasmic tail.

• α1 and α2 domains: These form the antigen-binding groove, which, in the case of CD1D, is a deep, hydrophobic cleft well-suited for binding the hydrophobic tails of lipids and glycolipids. The groove is composed of hydrophobic amino acid residues that interact with the lipid acyl chains, while the polar head group of the lipid remains exposed for interaction with the T cell receptor (TCR).
• α3 domain: The α3 domain is responsible for binding to β2-microglobulin (β2m), stabilizing the complex, and is analogous to the α3 domain in MHC class I molecules.
• Transmembrane and cytoplasmic domains: The transmembrane domain anchors CD1D in the cell membrane, while the cytoplasmic tail contains motifs necessary for intracellular trafficking between the endoplasmic reticulum (ER), Golgi apparatus, and endosomal compartments.

Antigen-Binding Groove:

The antigen-binding groove of CD1D is structurally adapted to accommodate hydrophobic lipid antigens. It contains two deep pockets (A’ and F’) that bind the hydrocarbon chains of lipids. Unlike MHC class I molecules that bind peptides using hydrogen bonds, CD1D binds lipids primarily through hydrophobic interactions. This groove allows the hydrophobic tails of lipid antigens to be buried inside the protein, while the hydrophilic head of the lipid antigen is exposed for recognition by T cell receptors (TCRs) on NKT cells.

Intracellular Trafficking:

CD1D molecules are known to traffic between the cell surface and intracellular compartments, particularly the endosomes and lysosomes, where they encounter and bind lipid antigens. After lipid loading in endosomal compartments, CD1D returns to the cell surface to present these antigens to NKT cells. Specific sequences in the cytoplasmic tail of CD1D regulate this intracellular movement, ensuring that CD1D can sample lipids from both the extracellular environment and intracellular pathogens.

Classification and Subtypes

The CD1 family is divided into group 1 and group 2 isoforms based on their structural features and functions. Group 1 includes CD1A, CD1B, CD1C, and CD1E, while CD1D belongs to group 2.

• Group 1 CD1 molecules (CD1A, CD1B, CD1C) are involved in presenting exogenous lipid antigens to conventional T cells.
• Group 2 CD1 molecules (CD1D) primarily present both endogenous and exogenous lipid antigens to NKT cells, particularly invariant NKT (iNKT) cells, which express a semi-invariant T cell receptor.

CD1D is the sole group 2 CD1 molecule in humans and plays a unique role in bridging innate and adaptive immune responses through its interaction with NKT cells.

Function and Biological Significance

The primary function of CD1D is the presentation of lipid antigens to NKT cells. NKT cells recognize these lipid antigens through their invariant T cell receptors (iTCRs), which differ from the diverse TCRs found on conventional T cells. Once activated, NKT cells rapidly secrete a broad range of cytokines, including both pro-inflammatory cytokines like IFN-γ and TNF-α, as well as anti-inflammatory cytokines like IL-4 and IL-10. This allows NKT cells to play a dual role in immune regulation, promoting both immunity and tolerance depending on the context.

Key Functions:

• Host Defense: CD1D-NKT cell interactions are crucial in the immune response to intracellular pathogens, particularly lipid-containing pathogens such as mycobacteria, including Mycobacterium tuberculosis and Mycobacterium leprae, and fungi. NKT cells can detect pathogen-derived lipid antigens and initiate a rapid immune response, often faster than conventional T cells.
• Immune Regulation: In addition to fighting infections, NKT cells play a regulatory role in the immune system. By producing IL-4 and IL-10, NKT cells can help suppress excessive inflammatory responses, which is essential in preventing autoimmune diseases and maintaining immune homeostasis.
• Tumor Immunity: CD1D-restricted NKT cells are involved in tumor immunosurveillance, recognizing tumor-derived glycolipids and initiating anti-tumor responses. This makes CD1D an attractive target in cancer immunotherapy.
• Autoimmunity: The regulatory role of CD1D and NKT cells extends to autoimmune conditions. By promoting the secretion of anti-inflammatory cytokines, NKT cells can help modulate autoimmune reactions and maintain self-tolerance.

Clinical Issues

Infectious Diseases:

CD1D plays a pivotal role in the defense against mycobacterial infections and other intracellular pathogens. Defects or polymorphisms in CD1D expression or function could impair the ability of the immune system to recognize lipid antigens from pathogens, resulting in susceptibility to chronic infections, particularly those caused by Mycobacterium tuberculosis.

Autoimmune Diseases:

CD1D and NKT cells are involved in the regulation of autoimmune diseases, such as type 1 diabetes (T1D), multiple sclerosis (MS), and systemic lupus erythematosus (SLE). NKT cells can modulate the immune response, preventing the activation of autoreactive T cells. Deficiencies in NKT cell function or altered CD1D expression may contribute to the pathogenesis of these diseases, where the immune system mistakenly attacks the body’s own tissues.

Cancer:

CD1D has gained attention in the field of cancer immunotherapy due to its role in tumor immunity. NKT cells can recognize and respond to lipid antigens derived from tumor cells, and CD1D-based immunotherapies aim to enhance this recognition. However, some tumors may evade immune detection by downregulating CD1D expression, suggesting a mechanism of immune evasion.

Therapeutic Potential:

CD1D represents a potential target for therapeutic interventions in infectious diseases, autoimmune disorders, and cancer. Approaches to modulate CD1D expression or enhance its antigen-presenting function are being investigated. Furthermore, CD1D agonists, such as synthetic lipid analogs (e.g., α-galactosylceramide), have shown promise in activating NKT cells to boost immune responses in clinical settings, including cancer immunotherapy.

Summary

The CD1D molecule is an essential component of the immune system, responsible for presenting lipid and glycolipid antigens to natural killer T (NKT) cells. Structurally similar to MHC class I molecules, CD1D is adapted to bind lipid antigens in its deep, hydrophobic binding groove. It interacts predominantly with invariant NKT (iNKT) cells, bridging innate and adaptive immune responses through the rapid secretion of cytokines. CD1D-NKT cell interactions are crucial in host defense against lipid-containing pathogens, immune regulation, tumor immunity, and autoimmunity. The therapeutic potential of targeting CD1D in diseases such as cancer, autoimmune disorders, and infectious diseases is of significant interest in the field of immunology.