Recognition features and functions
Unlike myeloid cells (macrophages, neutrophils), NK cells do not recognize PAMPs (pathogen-associated molecular patterns). Unlike classical T and B lymphocytes, they lack antigen-specific receptors encoded by rearranged genes. As a result, the natural killer population lacks a clonal structure — all cells are identical in the structure of key receptors.
NK cells recognize endogenous stress molecules (danger signals). Their mechanism of action is based on polyclonal recognition of cellular stress markers combined with «self-nonself» control (evaluation of target cell MHC-I molecule expression).
Main functions:
- Cytotoxic activity: directed against transformed (tumor), virus-infected, or severely stressed cells.
- Cytokine secretion: primarily IFNγ, which plays a critical role in regulating immune processes.
Morphology and granular apparatus
Visually, natural killer cells are described as large granular lymphocytes 10–12 µm in diameter with characteristic azurophilic granularity in the cytoplasm. The granules (100–500 nm in size) are essentially a type of lysosome with secretory vesicle features.
To execute cytolysis, mature granules contain specific proteins:
- Perforin: a 66–70 kDa protein, structural analogue of the terminal complement component C9. It polymerizes in a hydrophobic environment and forms pores in the target cell membrane.
- Granzymes (A, B, C): serine proteases. For instance, granzyme B, entering through perforin pores, triggers apoptosis in the target cell.
- Granulysin: a lipid-associated protein (active isoform — 9 kDa).
In addition to cytolytic proteins, the granules contain biogenic amines (histamine, serotonin), catecholamines (adrenaline, noradrenaline), proteoglycans (heparin, chondroitin sulfate), peptide hormones, and various enzymes (acid phosphatases, cathepsins).
NK cell subpopulations
Two main subpopulations are distinguished in humans based on the level of membrane expression of CD56 and CD16 markers (where hi stands for high and lo for low expression).
| Sign | Effector (CD56lo CD16+) | Regulatory (CD56hi CD16-) |
|---|---|---|
| Localization | Bloodstream (90–95%) | Tissues (liver, lymph nodes, endometrium) |
| Developmental stage | Terminal | Intermediate |
| Function | High cytotoxicity | Robust cytokine production (IFNγ, TNFα, IL-10) |
| IL-2 receptor | Low-affinity (β and γ chains) | High-affinity (α chain, CD25) |
| Proliferation | Weak (only at high IL-2 doses) | Intense (in response to IL-2 in vitro) |
Note: neither CD56 (a homophilic adhesion molecule) nor CD16 (the low-affinity FcγRIII receptor) is strictly specific to NK cells alone. They are found on neural cells, monocytes, and neutrophils.
Cell development
The population develops in the bone marrow. The parent cell is the common lymphoid progenitor (CLP), which also gives rise to T and B lymphocytes. At the lineage divergence stage, a pool of cells with dual potential is preserved — pre-T/NK cells (T/NKP).
The bone marrow microenvironment is critically important for successful differentiation:
- Direct contacts: interaction of membrane lymphotoxin α with stromal cell receptors.
- Cytokines: in vitro maturation requires a mixture of IL-7, IL-15, and Flt-3 ligand.
Briefly: answers to topical questions
What functions do granulysin and cathepsins perform in NK cell granules?
Granulysin contributes to triggering apoptosis via the sphingomyelin pathway. Cathepsins are components of additional NK cell granule constituents and belong to the enzyme family.
Which NK cell receptors are responsible for recognizing MHC-I molecules on target cells?
MHC-I molecules on target cells are recognized by inhibitory KIR receptors, CD94/NKG2 and LILR receptors, as well as the Ly49 family of receptors in mice. The main KIR group recognizes allelic variants of MHC-I molecules.
What cellular stress markers are recognized by activating NK cell receptors?
Activating NK cell receptors recognize endogenous stress molecules, such as non-classical stress proteins MICA and MICB, as well as ULBP proteins, which are expressed on transformed or infected cells.
How is antibody-dependent cellular cytotoxicity (ADCC) mediated by NK cells carried out?
Antibody-dependent cellular cytotoxicity is triggered when NK cells recognize antibodies bound to a target cell. This recognition occurs via low-affinity Fc receptors FcγRIII (CD16) on NK cells, which bind to the Fc fragments of IgG1 and IgG3 antibody subclasses acting as a "bridge" between the killer and the target.
Class and exam questions
What is the main difference between NK cells and other lymphocytes?
In the absence of antigen-specific receptors assembled via gene rearrangement. Consequently, NK cells lack a clonal structure.
What other lymphoid cells belong to the innate immunity?
The group of so-called "innate-like cells" also includes γδ T cells, NKT cells, and B1 lymphocytes.
What happens in case of genetic defects of CD3ε?
Defects affecting the genes of membrane molecules CD3ε block the normal development of common progenitor cells (T/NKP cells).
What else to study on this topic
- Molecular mechanism of "self-nonself" control (interaction with MHC-I)
- Antibody-dependent cellular cytotoxicity (ADCC) and the role of CD16
- Specific receptors: KIR, NKG2A, NKG2D, NKp30, NKp46
- Features of LAK cells (lymphokine-activated killer cells)
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