Sechenov School
Home › Pathology › Natural Killer Cells

Natural Killer Cells

Natural killer cells (NK cells)

For medical students2 min readUpdated 2026-10-10

Natural killer cells (NK cells) represent the third lymphocyte population, providing cell-mediated cytotoxic immune responses. They serve as a crucial immune surveillance barrier, rapidly eliminating damaged, malignant, and virus-infected cells.

MorphologyMedium-sized lymphocytes containing characteristic cytoplasmic granules.
SpecificityAct without prior antigen sensitization and are completely independent of the major histocompatibility complex (MHC).
ClassificationBelong to the group of "null cells" because they lack surface markers typical of T and B lymphocytes.
Main FunctionFirst line of defense against virus-infected, damaged, and tumor cells.

Classification and Morphological Features

Natural killer cells are classified as a distinct, third lymphocyte population (alongside T and B cells). In older medical literature, they are referred to as large granular lymphocytes. Morphologically, they are medium-sized cells characterized by the presence of specific granules in their cytoplasm.

In modern immunological classification, NK cells are categorized as "null cells". This designation stems from the complete absence of surface markers typically used to identify classical T or B lymphocytes.

Mechanism of Cytotoxic Action

The primary role of natural killer cells is to mediate cellular immunity through direct cytotoxic effects on target cells. While functionally similar to classical cytotoxic T lymphocytes (CTLs), their recognition system differs fundamentally:

Killer activity is triggered via an alternative pathway that directly depends on the recognition of specific differentiation antigens on the target cell surface.

Main Physiological Functions

Natural killer cells perform a vital barrier function, acting as the "first line" of immune surveillance to maintain internal homeostasis.

Key functions of NK cells include:

  1. Direct destruction of virus-infected cells.
  2. Elimination of tumor (transformed) cells.
  3. Clearance of damaged autologous cells.
  4. Nonspecific regulation of hematopoiesis and lymphopoiesis.

K-Cells: A Related Population

Alongside classical NK cells, another related killer cell lineage exists: K cells (killer cells). They share several characteristics with NK cells but utilize a unique operational mechanism.

Like natural killer cells, K cells lack T and B cell markers and are therefore also classified as null cells.

Their key distinguishing feature is the presence of surface Fc receptors. These structures allow K cells to exert cytotoxic effects via antibody-dependent mechanisms, making them essential for destroying targets pre-coated with specific antibodies.

Comparative Characteristics of Cytotoxic Cells

Based on their mechanisms, three distinct cytotoxic cell populations can be differentiated:

Mnemonic

To easily remember the differences between NK cells and T killers, use the rule of the "Two Ns": Natural killer cell cytotoxicity is Not MHC-restricted and Not antigen-specific. K cells can be remembered by the letter K—they work in Komplex with antibodies (possessing Fc receptors).

Frequently asked questions

Which molecules do NK cells use to disrupt target cell membranes?

Natural killer cells disrupt target cell membranes using the protein perforin.

  • Perforin — a 66–70 kDa protein that undergoes conformational change in the presence of calcium ions, exposing a hydrophobic domain.
  • Mechanism of action — molecules insert into the target cell membrane and polymerize (groups of 10–20), forming pores 10–20 nm in diameter.

Water and ions enter the cell through these perforin channels, causing osmotic shock and necrosis, alongside granzymes and granulysin, which trigger a caspase cascade and induce apoptosis.

Which CD markers are characteristic of natural killer cells?

Natural killer cells express specific surface molecules while lacking typical T and B lymphocyte markers.

Key human NK cell CD markers:

  • CD56 — homophilic adhesion molecule.
  • CD16 (FcγRIII) — low-affinity Fc receptor for IgG, involved in antibody-dependent cellular cytotoxicity.
  • CD94 — a component of inhibitory receptors.
  • CD2 — an accessory marker expressed on the surface of null lymphocytes.

Based on CD56 and CD16 expression levels, effector ($CD56^{lo} CD16^+$) and regulatory ($CD56^{hi} CD16^-$) subpopulations are distinguished.

Which membrane receptors control the activation of NK cells?

NK cell activation is governed by a balance of signals from activating and inhibitory membrane receptors.

  • Activating receptors recognize stress-induced molecules on target cells. These include NKG2D, NCR, CD16 (FcγRIII), and certain KIR family receptors—such as KIR3DS and KIR2DS. Activating receptors transmit signals via adaptor proteins containing ITAM or YXXM motifs.
  • Inhibitory receptors recognize MHC class I molecules and prevent autologous cell lysis. They contain an immunoreceptor tyrosine-based inhibitory motif (ITIM). Examples include CD94/NKG2 heterodimers (e.g., NKG2A), LILR (LIRLB1), and most KIR receptors (KIR3DL and KIR2DL).
Which cytokines stimulate the proliferation and activity of natural killer cells?

Natural killer cell proliferation is stimulated by interleukin-2.

  • Interleukin-2 (IL-2) is secreted by Th1 cells and drives NK cell expansion.
  • Effector NK cells express an IL-2 receptor composed of $\beta$ and $\gamma$ chains with intermediate affinity, resulting in weak proliferation except at high IL-2 concentrations.
How do NK cells recognize the absence of MHC class I on target cells?

Natural killer cells detect MHC class I deficiency using membrane inhibitory receptors via the "missing self" hypothesis.

  • Inhibitory signal: NK cell receptors of the KIR, CD94/NKG2, and LILR families bind to MHC-I molecules on healthy cells, suppressing cytolysis.
  • Activation: If MHC-I molecules are absent on a target cell, the inhibitory signal fails. In the presence of activating stress ligands on the target, the balance shifts toward activation, and the NK cell destroys the target.
Which lymphocyte population do natural killer cells belong to?

Natural killer (NK) cells constitute a distinct, third lymphocyte population functioning alongside the T and B cell populations.

Why are NK cells and K cells called "null cells"?

This term reflects the complete absence of surface markers typically used in laboratory diagnostics to identify classical T and B lymphocytes.

How do NK cells differ from cytotoxic T lymphocytes (CTLs)?

Although they share a similar cytotoxic mechanism, NK cell activity is not restricted by the major histocompatibility complex (MHC) and is non-antigen-specific. They recognize targets via differentiation antigen profiles.

What is the main difference in the mechanism of action between K cells and NK cells?

K cells possess specific Fc receptors on their membrane, allowing them to mediate antibody-dependent cellular cytotoxicity, whereas NK cells function independently of antibodies.

Go deeper

More topics in Pathology

International Classification of DiseasesBirth Injury: Types, Pathophysiology and Clinical PresentationCarbohydrate DystrophiesMacroscopic Appearance of NecrosisStages of Compensatory and Adaptive ProcessesPlasma Inflammatory MediatorsRheumatic GranulomaLocal Venous HyperemiaEtiology and Pathogenesis of Essential HypertensionRapidly Progressive GlomerulonephritisPulmonary AtelectasisBarrett's EsophagusPathology →