Classification and morphological features
Natural killers are classified into a separate, third population of lymphocytes (along with T and B cells). In historical medical literature, their obsolete name — large granular lymphocytes — can be found. Morphologically, these are medium-sized cells whose distinguishing feature is the presence of specific granules in the cytoplasm.
In modern immunological classification, NK cells are generally classified as a special group of so-called «null cells» (null cells). This name is due to the fact that their membrane completely lacks the typical surface markers used to identify classical T lymphocytes or B lymphocytes.
Mechanism of cytotoxic action
The main task of natural killers is to execute a cell-mediated response through direct cytotoxic action on the target cell. Essentially, this process is identical to the work of classical cytotoxic T lymphocytes (CTLs), but it has fundamental differences in the recognition system.
- MHC independence: unlike CTLs, the cytotoxicity of NK cells is not restricted by the major histocompatibility complex (MHC). This means they do not require preliminary antigen presentation.
- Lack of antigen specificity: the action of natural killers is not antigen-specific.
Killer activity is triggered through a different pathway — it directly depends on the recognition of a specific group of differentiation antigens on the surface of the target cell.
Main functions in the body
Natural killers perform a vital barrier function, acting as the «first line» of immune surveillance in the body. Their activity is aimed at maintaining the genetic homeostasis of the internal environment.
Key tasks of NK cells include:
- Direct destruction of virus-infected cells.
- Elimination of tumor (transformed) cells.
- Elimination of any damaged cells of the body.
- Nonspecific regulation of hematopoiesis and lymphoid tissue development (lymphopoiesis).
K cells: a related population
In addition to classical NK cells, there is another related lineage of killer cells — K cells. They share a number of similar characteristics, but have their own unique mechanism of action.
Like natural killers, K cells lack T- and B-cell markers, and are therefore also classified as «null lymphocytes» (null cells).
Their main distinguishing feature is the presence of Fc receptors on the membrane. Thanks to these structures, K cells are able to exert a killer effect via antibody-dependent mechanisms. This makes them an essential tool for destroying targets previously coated with specific antibodies.
Comparative characteristics of killer cells
Based on the described mechanisms, three types of cells possessing cytotoxicity during an immune response can be clearly distinguished:
- Cytotoxic T lymphocytes (CTLs): possess strict antigen specificity, and their action is strictly restricted by the MHC complex.
- Natural killer (NK) cells: execute the same cytotoxic mechanism as CTLs, but their action is not restricted by the MHC, is not antigen-specific, and depends on the recognition of a group of differentiation antigens.
- K cells: related to NK cells, also classified as null lymphocytes, but possess Fc receptors and kill targets exclusively via antibody-dependent mechanisms.
Briefly: answers to topical questions
Which molecules do NK cells use to destroy the membrane of a target cell?
Natural killer cells destroy the membrane of the target cell using the protein perforin.
- Perforin is a protein with a molecular weight of 66–70 kDa that changes conformation in the presence of calcium ions, exposing a hydrophobic region.
- Mechanism of action: the molecule embeds itself in the target membrane and polymerizes (10–20 molecules together), forming a pore 10–20 nm in diameter.
Water and ions enter the cell through the formed perforin channels, causing osmotic shock and necrosis, along with granzymes and granulysins, which trigger a caspase cascade and induce apoptosis.
Which CD markers are characteristic of natural killer cells?
Natural killer cells are characterized by the presence of specific surface molecules in the absence of typical T- and B-lymphocyte markers.
Main CD markers of human NK cells:
- CD56 is a homophilic adhesion molecule.
- CD16 (FcγRIII) is a low-affinity receptor for the Fc fragment of IgG, involved in antibody-dependent cellular cytotoxicity.
- CD94 is a component of inhibitory receptors.
- CD2 is an additional marker expressed on the surface of null lymphocytes.
Depending on the level of CD56 and CD16 expression, effector (CD56lo CD16+) and regulatory (CD56hi CD16-) subpopulations are distinguished.
What types of receptors on the NK cell membrane control their activation?
The activation of natural killer cells is controlled by the balance of signals from activating and inhibitory membrane receptors.
- Activating receptors recognize stress-induced molecules on target cells. These include NKG2D, NCR, CD16 (FcγRIII), as well as certain KIR group receptors, such as KIR3DS and KIR2DS. Activating receptors can transmit signals via adaptor proteins containing ITAM or YXXM motifs.
- Inhibitory receptors recognize MHC-I molecules and prevent the cytolysis of self-cells. They contain an inhibitory ITIM motif. These include CD94/NKG2 group receptors — for example, NKG2A, LILR (LIRLB1), and most KIR receptors — KIR3DL and KIR2DL.
Which cytokines stimulate the proliferation and activity of natural killer cells?
The proliferation of natural killer cells is stimulated by interleukin-2.
- Interleukin-2 (IL-2) is secreted by Th1 cells and induces the proliferation of NK cells.
- In effector NK cells, the IL-2 receptor consists of β and γ chains and exhibits intermediate affinity. Therefore, the cells proliferate weakly and only at high concentrations of IL-2.
How do NK cells recognize the absence of class I MHC on a target cell?
Natural killer cells recognize the absence of MHC-I via membrane inhibitory receptors as part of the missing self concept.
- Inhibitory signal: NK cell receptors of the KIR, CD94/NKG2, and LILR groups bind to MHC-I molecules on cells, suppressing cytolysis.
- Activation: if MHC-I molecules are absent on the target cell, no inhibitory signal is received. If activating stress molecules are present on the target, the signal balance shifts toward activation, and the NK cell damages the target cell.
To easily remember the differences between NK cells and cytotoxic T cells, use the "Two NOs" rule: natural killer cell cytotoxicity is NOT MHC-restricted and is NOT antigen-specific. And K cells are easy to remember by the letter "K" — they work in a Complex with antibodies (they have Fc receptors).
Class and exam questions
Which lymphocyte population do natural killer cells belong to?
Natural killer (NK) cells are classified as an independent, third lymphocyte population that functions alongside the more well-known first and second populations—T and B cells.
Why are NK cells and K cells called "null cells"?
This name is due to the complete absence on their surface of typical markers used in laboratory diagnostics to identify classical T lymphocytes and B lymphocytes.
How do NK cells differ from cytotoxic T lymphocytes (CTLs)?
Although they implement the same mechanism of cytotoxicity, the action of NK cells is not restricted by the major histocompatibility complex (MHC) and is not antigen-specific. They recognize targets based on groups of differentiation antigens.
What is the main difference in the mechanism of action between K cells and NK cells?
K cells have specific Fc receptors on their membrane. Due to this, their killer action is realized via antibody-dependent mechanisms, whereas NK cells work independently of antibodies.
What else to study on this topic
- The detailed mechanism of how NK cells recognize groups of differentiation antigens.
- The process of nonspecific regulation of lymphopoiesis and hemopoiesis by natural killer cells.
- Stages of antibody-dependent killer action of K cells via Fc receptors.
- Contents of cytoplasmic granules in NK cells and the biochemistry of cytotoxicity.
- The relationship between the barrier function of NK cells and antitumor immune surveillance.
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