C-type Lectin Receptors

C-type Lectin Receptors Background

About C-type Lectin Receptors

C-type lectin receptors (CLRs) are a family of pattern recognition receptors (PRRs) involved in the recognition and response to pathogens in the immune system. They are named after their characteristic carbohydrate recognition domain (CRD), which allows them to bind to specific sugar structures, including mannose, fucose, and glucan, present on pathogen surfaces. CLRs play a crucial role in both innate and adaptive immune responses.

CLRs are transmembrane proteins that consist of one or more CRDs, a stalk region, a transmembrane domain, and a cytoplasmic tail. The CRD is responsible for carbohydrate recognition and binding. Based on structural and functional characteristics, CLRs are classified into several subfamilies, including:

  • Endocytic CLRs: These receptors, such as mannose receptor (MR) and dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN), mediate the internalization of pathogens for antigen presentation and immune activation.
  • Signaling CLRs: These receptors, such as Dectin-1 and Dectin-2, contain immunoreceptor tyrosine-based activation motifs (ITAMs) or immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in their cytoplasmic tails. They trigger signaling pathways upon ligand binding, leading to immune cell activation or inhibition
  • Soluble CLRs: Some CLRs, like mannose-binding lectin (MBL) and surfactant proteins, are secreted proteins that circulate in the bloodstream. They recognize pathogens and activate the complement system, enhancing opsonization and phagocytosis.

Functions of C-type Lectin Receptors

Pathogen Recognition: CLRs recognize a wide range of pathogens, including bacteria, fungi, viruses, and parasites. They detect specific carbohydrate structures present on the surface of these pathogens, enabling immune cells to identify and respond to potential threats.

Immune Cell Activation: CLRs on immune cells, such as macrophages, dendritic cells, and neutrophils, can trigger immune responses upon ligand binding. This includes the release of pro-inflammatory cytokines, chemokines, and antimicrobial peptides, as well as the activation of phagocytosis, antigen presentation, and T-cell priming.

Modulation of Immune Responses: CLRs can also regulate immune responses by delivering inhibitory signals. Some CLRs have ITIMs in their cytoplasmic tails, which recruit inhibitory signaling molecules to dampen immune cell activation. This modulation helps maintain immune tolerance and prevent excessive inflammation.

Antigen Presentation: CLRs expressed on dendritic cells are involved in capturing and processing antigens for presentation to T cells. This interaction initiates adaptive immune responses and influences T-cell differentiation and activation.

C-type lectins function in innate immune responses and have a dual function in pathogen recognition and cell adhesion.Fig. 1 C-type lectins function in innate immune responses and have a dual function in pathogen recognition and cell adhesion. (Varki A, et al., 2009)
Lectins expressed on dendritic cells (DCs) and macrophages interact with free pathogen-derived glycans or directly with pathogens, which can lead to pathogen adhesion and possibly internalization if the pathogen is single-celled. Activation of C-type lectins such as DC-SIGN and dectin-1 potentiates cytokine production by DCs. Interactions of pathogens with toll-like receptors (TLRs, such as TLR-2 and TLR-4) can directly activate DCs and macrophages, leading to release of cytokines such as interferon-γ and IL-12, and up-regulation of factors that stimulate T cells. C-type lectins on DCs and macrophages can synergize or antagonize TLR signals, depending on the glycan and pathogen. For example, mycobacterium-derived mannosylated lipoarabinomannans bind to DCs via the macrophage mannose receptor (MMR) and DC-SIGN, which inhibit TLR-mediated IL-12 production. Thus, simultaneous binding of ligands to TLRs and C-type lectins might produce a tolerogenic Th2 response rather than a protective Th1 response. Lectins can bind to specific ligands such as ICAM-2, CD34, and PSGL-1 to promote endothelial and T-cell interactions.

Pathophysiology of C-type Lectin Receptors

The pathophysiology of CLRs involves their role in the recognition of pathogens and the subsequent immune response. Abnormalities in CLR signaling or function can have significant implications for immune system function and disease development. Here are some key aspects of the pathophysiology of CLRs:

  • Pathogen Recognition: CLRs are involved in the recognition of various pathogens, including bacteria, fungi, viruses, and parasites. These receptors bind to specific carbohydrate structures on the surface of pathogens, initiating immune responses. However, certain pathogens have evolved mechanisms to evade or subvert CLR recognition, enabling them to escape immune detection and establish infection.
  • Immune Cell Activation: Upon ligand binding, CLRs can trigger signaling pathways that lead to immune cell activation. This activation includes the production of pro-inflammatory cytokines, chemokines, and antimicrobial peptides. It also promotes phagocytosis, antigen presentation, and the activation of adaptive immune responses. Dysregulation of CLR signaling can result in either excessive or inadequate immune activation, leading to immune-related disorders.
  • Inflammation and Autoimmunity: Abnormalities in CLR signaling can contribute to chronic inflammation and autoimmune diseases. Dysregulated activation of immune cells through CLRs can lead to the sustained production of pro-inflammatory cytokines and chemokines. This chronic inflammatory state can damage tissues and promote the development of autoimmune conditions.
  • Allergic Reactions: Some CLRs, such as mannose receptor (MR) and dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN), are involved in allergen recognition and immune responses. In allergic reactions, aberrant activation of CLRs by allergens can trigger an exaggerated immune response, resulting in allergic symptoms such as respiratory distress, skin reactions, and anaphylaxis.
  • Host-Pathogen Interactions: CLRs play a crucial role in host-pathogen interactions. Pathogens can manipulate CLR recognition to evade immune responses. For example, certain fungal pathogens produce surface molecules that mimic host carbohydrates to evade CLR-mediated recognition. Understanding these interactions is important for developing strategies to enhance immune responses against pathogens.
  • Cancer Immunology: CLRs also have implications in cancer immunology. Some CLRs, such as Dectin-1, have been implicated in anti-tumor immune responses. Activation of CLRs on immune cells can promote tumor antigen recognition, immune cell recruitment, and tumor cell killing. However, tumors can exploit CLR signaling to evade immune surveillance and promote immune tolerance, contributing to tumor progression.
  • Genetic Deficiencies: Inherited genetic deficiencies or mutations in CLR genes can lead to impaired immune responses and increased susceptibility to infections. For example, mutations in the mannose-binding lectin (MBL) gene can result in reduced MBL production, compromising the activation of complement pathways and increasing the risk of infections.

Understanding the pathophysiology of CLRs is critical for elucidating their roles in immune responses, infectious diseases, autoimmunity, cancer, and other disorders. Further research in this field can lead to the development of targeted therapies and immunomodulatory strategies to enhance immune responses or mitigate immune-related diseases.

C-type lectin receptors (CLRs) shape innate and adaptive immune responses. Fig. 2 C-type lectin receptors (CLRs) shape innate and adaptive immune responses. (Bermejo-Jambrina M, et al., 2018)
Certain CLRs contain ITIM domains and signal via SHP1 and SHP2 phosphatases, whereas other CLRs signal via their ITAM motif. DC-SIGN signaling is carbohydrate specific (CRD) and either signals via Raf-1 signalosome or IKKε and de-ubiquitinase CYLD, with distinct outcomes. MDL1 signals via DAP12 and Syk.

Available Resources for C-type Lectin Receptors

Creative BioMart offers a wide range of quality tools related to CLR, including recombinant proteins and more. We provide personalized services according to the specific needs of our clients. In addition, we provide comprehensive resources covering all aspects of CLR, including involved pathways, protein functions, interacting proteins, related articles, and other relevant topics to help advance CLR-related research.

Human CD69 transmembrane C-Type lectin protein - Creative BioMart

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References:

  1. Varki A, Cummings RD, Esko JD, et al., eds. Essentials of Glycobiology. 2nd ed. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 2009.
  2. Bermejo-Jambrina M, Eder J, Helgers LC, et al. C-Type Lectin Receptors in Antiviral Immunity and Viral Escape. Front Immunol. 2018;9:590. Published 2018 Mar 26. doi:10.3389/fimmu.2018.00590
  3. Mnich ME, van Dalen R, van Sorge NM. C-Type Lectin Receptors in Host Defense Against Bacterial Pathogens. Front Cell Infect Microbiol. 2020;10:309. Published 2020 Jul 7. doi:10.3389/fcimb.2020.00309
  4. Geijtenbeek TB, Gringhuis SI. Signalling through C-type lectin receptors: shaping immune responses. Nat Rev Immunol. 2009;9(7):465-479. doi:10.1038/nri2569
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