Scavenger receptors and C-type lectin receptors

Molecules similar to scavenger receptors and integrins

Scavenger receptors (scavenger receptors) play a critical role in antibacterial defense. With a genetic defect or "knockout" of the genes for these molecules, the body loses the ability to effectively combat infections caused by neisseriae and listeriae.

The group of pattern recognition molecules structurally or functionally similar to scavenger receptors includes:

• MARCO — functions as an adhesion molecule.
• CD14 — a classical marker of monocytes and macrophages. The specific feature of this receptor is that it attaches to the cell membrane via a glycosylphosphatidylinositol (GPI) anchor. Its main task is the recognition of lipopolysaccharide (LPS) and other lipid components in conjunction with Toll-like receptors (TLRs).
• CD36 — a molecule responsible for the clearance of self-tissues. It mediates the phagocytosis of cells that have died via apoptosis.

In addition, some classical adhesion molecules—integrins—are also classified among innate immunity receptors. Certain representatives of this group act as complement system receptors. In particular, molecules binding the complement component C3b:

• β2-integrin CD11b/CD18 (αMβ2), known as the CR3 receptor.
• β2-integrin CD11c/CD18 (αXβ2), functioning as the CR4 receptor.

C-type lectin receptors (CL receptors): essence and localization

C-type lectin receptors are widely expressed on the surface of myeloid lineage cells. Their main task is to provide the cell with the ability for massive pinocytosis and phagocytosis.

The functionality of these molecules is based on two key properties:

1. High affinity for specific carbohydrate residues (acting as a pattern recognition receptor).
2. The ability to internalize, i.e., engulf the bound ligand for its subsequent digestion.

The highest density of CL receptors is observed on cells specialized in active antigen capture. These include immature myeloid dendritic cells (which actively pinocytose), as well as monocytes and macrophages (professional phagocytes). Interestingly, as myeloid dendritic cells mature, endocytosis intensity drops, accompanied by the loss of the vast majority of C-type lectin receptors from the membrane surface.

Structure and ligand recognition mechanism

The structure of this group of receptors is based on the C-type lectin-like domain — CTLD (C-type lectin-like domain). A single receptor molecule can contain from one to ten such domains. Upon contact with carbohydrates, receptors often assemble into dimers or oligomers for stronger binding.

Out of 17 described C-type lectin groups, only four undertake the pattern recognition function: group II (dectin-2, langerin, DC-SIGN), group III (collectins, including surfactant proteins A and D), group V (dectin-1), and group VI (DEC-205, macrophage mannose receptor).

Specificity and calcium dependence:

• Most CL receptors are "classical", meaning they are capable of binding carbohydrates exclusively in the presence of calcium ions (Ca2+).
• Exceptions include calcium-independent lectins, for example, dektin-1, which is structurally similar to NK cell receptors.
• Most often, receptors recognize microbial carbohydrate structures containing mannose residues. Fucose, glucose, and N-acetylglucosamine are targeted less frequently. Specificity directly depends on the domain's ability to recognize certain regions of branched carbohydrate chains.
• An important nuance: the mere presence of the CTLD domain does not guarantee the ability to bind sugars. For instance, the carbohydrate specificity of the DEC-205 receptor remains unknown to this day.

Mechanism of immunological tolerance: It is critically important how C-type lectins distinguish foreign molecules from self. The secret lies in the fact that vertebrate cell membrane proteins and lipids are rich in sialylated sugar residues, whereas CL receptors do not recognize them. Thanks to this, phagocytes selectively capture only microbial polysaccharides while ignoring healthy self-tissues.

Intracellular fate and signal transduction

The main purpose of myeloid cell lectin receptors is antigen uptake and its delivery inside the cell for degradation. Unlike many other pattern recognition molecules, transmitting an activating signal to the nucleus is not an obligatory function for them.

Endocytosis of receptor-ligand complexes is triggered by special intracellular internalization motifs:

• Tyrosine-based motif (found, for example, in the macrophage mannose receptor). It ensures the ligand is submerged only to the early endosome stage. After this, the receptor quickly detaches and returns (recycles) back to the cell membrane.
• Dileucine motif and triacidic cluster (characteristic of DEC-205, DC-SIGN, dectin-1). They direct the engulfed material into deep layers of the cell—all the way to late endosomes and vesicles where MHC class II (MHC-II) molecules are stored. This is necessary for the high-quality preparation of the antigen for presentation to T lymphocytes.

Among all carbohydrate-recognition receptors, dectin-1 stands apart. It is the only molecule in the group that has a fully functional ITAM (Immunoreceptor tyrosine-based activation motif) activation motif in its intracellular part. The presence of ITAM allows dectin-1 not only to capture antigens but also to independently transmit a powerful activating signal into the cell.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Structure and functions of the macrophage mannose receptor (MR/CD206)
• The DEC-205 molecule (CD205) and its role in antigen presentation
• The role of dectin-1 in defense against infections (recognition of β-glucan)
• Interaction of CD14 with Toll-like receptors (TLRs) in LPS recognition
• Classification of adhesion molecules: structure and function of integrins

Other topics in the "Innate Immunity" section

Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.