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Immunology · Innate Immunity

NK cell receptors

NK cell receptors

Natural killer (NK cell) receptors are structures on the surface of lymphocytes that determine the recognition of self, foreign, or altered cells. They are divided into activating and inhibitory receptors, and the balance of their signals determines whether the target cell will be destroyed.

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GeneticsMost are encoded within the NK gene complex on chromosome 12.
ClassificationActivating (transmit a signal) and inhibitory (inhibit cytolysis).
Main markerRecognize MHC-I molecules as a "self" cell marker.
Stress signalThe activating receptor NKG2D responds to MIC and ULBP molecules.
3 min readFor medical studentsUpdated Sep 25, 2026
Material prepared by WhiteCoat Pro editorial team based on platform study guidesReviewed by medical editor: Aulov A. A., general practitioner · 09/24/2026

Main receptor families

Based on the resulting effect, receptors are divided into inhibitory (inhibiting cytolysis) and activating. Interestingly, receptors with opposing functions can belong to the same family.

  • KIR family (Killer cell Immunoglobulin-like Receptors). Includes inhibitory (e.g., KIR2DL1, KIR3DL1) and activating (KIR2DS1, KIR3DS1) receptors. The main ligands are HLA molecules.
  • CD94/NKG2 family. Includes both inhibitory (CD94/NKG2A) and activating (CD94/NKG2C) variants that respond to HLA-E.
  • NKG2D receptor. A crucial activating receptor that responds to stress-induced molecules (MIC A/B, ULBP).
  • LILR family (Leukocyte Immunoglobulin-like Receptors). Inhibitory receptors (LILRB1, LILRB2).
  • FcR family. For example, FcγRIII (CD16) is an activating receptor that binds IgG1 and IgG3.
  • NCR family (Natural Cytotoxicity Receptors). Activating receptors (NKp46, NKp30, NKp44) whose ligands have not yet been identified.

Structure and signal transduction mechanisms

The function of a receptor (activating or inhibitory) depends on specific motifs located in the cytoplasmic domain of the receptor itself or in an associated polypeptide chain.

  • Extracellular domain: consists of an immunoglobulin-like (Ig) or lectin domain that recognizes ligands.
  • Inhibitory receptors: contain an intracellular ITIM motif (Immunoreceptor tyrosine-based inhibitory motif). They block cell activation.
  • Activating receptors: are associated with adaptor proteins that carry ITAM (Immunoreceptor tyrosine-based activation motif) or YXXM motifs.

For example, the NKG2D receptor is associated with the DAP-10 adaptor protein containing a YXXM motif. Upon ligand binding, the tyrosine in this motif is phosphorylated, recruiting the lipid kinase PI₃K. This triggers an activation cascade leading to cytolysis.

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Activating NKG2D receptor and its ligands

NKG2D is a homodimeric type II transmembrane protein (C-terminus directed outwards) belonging to C-type lectins. It is expressed on all NK cells and some T lymphocytes.

Its primary ligands are stress-induced molecules that are not presented on healthy cells. They appear only upon transformation, viral infection, or other stress:

  1. MIC molecules (MICA, MICB). Similar to MHC-I, but lack $\beta_2$-microglobulin and a peptide-binding groove. Do not participate in antigen presentation.
  2. ULBP proteins (1–4). Also similar to MIC, but have only two domains.

These molecules serve as a kind of "distress signal", forcing the NK cell to destroy the altered or infected cell.

How to memorize

Activating motifs have the letter "A" in their name (ITAM - Activation), while inhibitory ones have "I" (ITIM - Inhibitory).

Class and exam questions

How do MIC molecules differ from classical MHC-I molecules?

Unlike MHC-I, MIC molecules do not contain associated $\beta_2$-microglobulin and lack a special groove for peptide binding. They do not present antigens.

Where are ligands for the NKG2D receptor expressed?

MIC and ULBP ligands are expressed exclusively on transformed, virus-infected, or severely stressed cells.

Which adaptor protein is required for NKG2D function?

For signal transduction, NKG2D electrostatically binds within the membrane to the DAP-10 adaptor protein, which contains an activating YXXM motif.

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What else to study on this topic

  • Stages of NK cell development and maturation (NKP, pre-NK)
  • The role of IL-15 in natural killer survival and homeostasis
  • Migration and distribution of mature NK cells in organs and tissues
  • Transcription factors (Id2, Ets1) defining the NK cell lineage

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