The "missing self" concept and response variants
The main function of inhibitory receptors is to prevent contact cytolysis of cells that carry normal MHC-I (major histocompatibility complex class I) molecules. This concept is termed "missing self". In modern immunology, it is believed that the fate of the target depends on the balance between inhibitory signals from MHC-I and activating signals from stress molecules.
Depending on which molecules are present on the target surface, four scenarios are possible:
- Variant A: Neither MHC-I nor the activating ligand is present. There is no response from the killer.
- Variant B: Only MHC-I is present. There is no response, as a strong inhibitory signal is triggered.
- Variant C: MHC-I is absent, but the activating ligand is present. Full activation and destruction of the target occurs.
- Variant D: Both MHC-I and the activating ligand are present. The outcome depends entirely on the balance of opposing signals received.
Inhibitory receptors
Cytolysis of autologous tissues is blocked by membrane receptors that recognize MHC-I molecules. They are divided into two main groups:
- KIR (Killer cell Ig-like receptor) group: Expressed on a subpopulation of CD56^dim^ cells (humans have 15 types, while they are poorly represented in mice). Inhibitory variants have a long cytoplasmic tail (L-variant) and contain an ITIM motif (formula: I/V/L/SXYXXL). They recognize widely distributed allelic forms, primarily HLA-C. For successful recognition, the MHC-I complex must be structurally complete.
- CD94/NKG2 and LILR group receptors: These are heterodimers consisting of a non-polymorphic CD94 chain and NKG2 variants (NKG2A, NKG2E, and NKG2F possess inhibitory properties). They recognize non-classical HLA-E molecules, which present fragments of the leader sequences of MHC-I proteins.
Activating receptors
Killer activation is triggered by the binding of specific ligands. The most important groups of activating receptors:
- Activating KIR receptors: Have a short cytoplasmic part (S-variant). They are associated with the DAP12 protein, which contains an activating ITAM motif (formula: YXXI/Lx(6–12)YXXI/L). Ligands for them are not always known, but, for example, KIR2DS2 recognizes certain HLA-C alleles.
- NCR (Natural cytotoxicity receptors) group: Includes poorly studied NKp46, NKp30, and NKp44 proteins. They react to stress molecules induced by viruses (e.g., influenza). NKp46 and NKp30 are expressed constitutively and associated with CD3ζ and FcεRIγ chains, whereas NKp44 appears only after IL-2 activation and is associated with the DP-12 chain.
- Stress proteins and antibodies: Receptors recognize induced proteins (e.g., the MIC group in tumors or NKG2D ligands). Also important is the Fc receptor FcγRIII (CD16), which mediates activation upon contact with targets opsonized by IgG antibodies.
Stages of contact cytolysis
NK cells perform contact cytolysis (unlike myeloid cells, which prefer phagocytosis). The process is divided into 4 successive stages:
- Recognition and contact formation: An immunological synapse forms within 1.5–2 minutes. The process strictly depends on Mg2+ ions. Adhesion molecules work first, then receptors come into play.
- Activation of natural killers: The interaction of activating receptors with ligands triggers the secretion of cytolytic molecules into the microcavity between cells or induces the expression of membrane death inducers.
- Programming of death (lysis): Granules with granzymes are delivered into the cell through pores formed by perforin, or a signal is transmitted via apoptotic receptors. Important: after this stage, it is impossible to save the target even if physical contact is broken.
- Target cell destruction: The final stage of executing programmed apoptosis or necrosis.
Briefly: answers to topical questions
Which cytokines induce the activation and proliferation of NK cells?
NK cell activation is induced by interleukin-2 (IL-2). Under the influence of this cytokine, natural killers are activated and transition into LAK cells. An additional activation receptor of the NCR group—the NKp44 protein—begins to be expressed on the surface of such lymphocytes. Unlike it, other receptors of this group (NKp46 and NKp30) are expressed constitutively on all NK cells. Information on cytokines directly inducing NK cell proliferation is not presented in the sources.
Through which mechanisms do tumor cells evade immune surveillance by NK cells?
Tumor cells evade NK cell immune surveillance by altering the expression of major histocompatibility complex molecules and secreting stress proteins. The following mechanisms are distinguished:
- Preservation of MHC expression (MHC-I) — NK lymphocyte activity is blocked by both classical and non-classical molecules.
- Perfect evasion — loss of classical MHC-I while retaining non-classical molecules, which completely blocks the killer response.
- Secretion of soluble ligands (MIC) — tumor cells can secrete stress proteins in a soluble form, leading to a weakened response to them.
What proteins are contained in NK cell cytotoxic granules besides perforin and granzymes?
Besides perforin and granzymes (in particular, granzyme B), NK cell cytotoxic granules contain granulysin. These granules participate in the execution of cytolysis. Perforin forms a transmembrane pore through which granzymes are delivered; after passing this stage, target cell death cannot be prevented.
How not to confuse KIR receptor types by tail length: S-variant — Short and Stimulating (contains ITAM). L-variant — Long and Limiting/Inhibitory (contains ITIM).
Class and exam questions
Why do tumors sometimes manage to escape destruction by NK cells?
During tumor development, stress proteins of the MIC group are induced. However, tumor cells can secrete them in a soluble form, leading to a weakened killer response to these molecules.
Does the expression of NCR receptors depend on the cell state?
Yes, partially. While NKp46 and NKp30 are constitutively expressed on all cells, NKp44 appears only after their activation by interleukin-2 (as LAK cells).
Can cell death be prevented if its contact with the killer is interrupted?
No. If the stage of cell death programming has already been passed (granzymes delivered or apoptotic signal transmitted), target destruction is inevitable, even if the cells are physically separated.
What else to study on this topic
- Features of viral protein recognition (using mouse m17 protein as an example)
- The role of tyrosine phosphatases (SHP1, SHP2, SHIP) in interrupting the activation signal
- The mechanism of opsonization and the function of the FcγRIII (CD16) receptor
- Differences in the receptor apparatus between mice (Ly49 family) and humans
- Structural independence of the NKG2D molecule from other NKG2 group proteins
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