Phenotype and antigen recognition
NKT cells have an "activated" phenotype and express markers on their membrane characteristic of activated T lymphocytes, such as CD69, CD95, and CD44. Their main feature is that their receptors (TCR) recognize antigens not in the context of classical MHC molecules, but in a complex with the CD1d molecule.
Ligands recognized by NKT cells are predominantly of lipid or glycolipid nature:
- Artificial (experimental): α-galactosylceramide (αGalCer) isolated from marine sponges. In laboratories, binding of the labeled CD1d-αGalCer complex is used to precisely identify invariant NKT cells.
- Natural (bacterial): ceramides, α-glucuronyl, and glycosphingolipids presented by dendritic cells.
- Autologous (endogenous): e.g., isoglobotriaosylceramide (iGB3).
Development and selection
The ontogeny of NKT cells takes place in the thymus, with T-cell features (TCR) appearing earlier than NK-cell properties. Lineage segregation occurs after TCR gene rearrangement with the choice of the Vα14/Vα24 segment.
An important stage is positive selection, which is carried out not by thymic stromal cells, but by cortical CD4+CD8+ thymocytes expressing CD1d.
Further maturation includes:
- Expression of the CD4 molecule and the transcription factor RORγt.
- Spontaneous secretion of IL-4 (predominant) and IFNγ cytokines.
- Reduction or loss of CD4 expression.
- Negative selection with the elimination of autoreactive clones.
- Agonist-dependent selection, due to which some cells retain affinity for self-ligands and acquire regulatory functions.
Before leaving the thymus, cells actively divide, while full NK activity and characteristic markers are acquired in the periphery.
Distribution and migration in the body
Survival (homeostasis) of NKT cells, like classical natural killers, depends on the IL-15 cytokine.
In peripheral blood and lymph nodes, their proportion is less than 1%, and in the spleen, it is about 2%. The main reservoirs are the liver and bone marrow.
NKT cell migration is strictly regulated by chemokine receptors:
- CXCR6: binds to CXCL16 (secreted by liver sinusoidal endothelial cells) and directs cells to the liver.
- CCR2: responds to MCP-1/CCL2 and ensures migration to the spleen.
- CCR7: allows cells to enter the T-zones of lymphoid organs.
Functions of NKT lymphocytes
Although NKT cells carry a T-cell receptor, they function as elements of innate immunity. Three key roles are distinguished:
- Early cytokine production: In the initial stages of infection, they are practically the sole source of IFNγ.
- Immune response regulation: Like regulatory T cells, they control the strength of the immune response, protecting the body from hyperergy and autoaggression.
- Cytotoxicity: The ability to directly destroy target cells.
Briefly: answers to topical questions
Which NKT cell subpopulations are distinguished based on the expression of CD4 and CD8 coreceptors?
- CD4+ fraction (CD4+CD8-) — an NKT cell subpopulation that continues to secrete IL-4 in the periphery.
- Double negative cells (CD4-CD8-) — an NKT cell population.
- CD4-/+ fraction (CD4-/+CD8-) — mature NKT cells expressing CD44 and NK1.1.
Through what molecular mechanisms do NKT cells exert their cytotoxicity?
- Perforin-granzyme mechanism (perforinum et granzymum) — the release of perforin and granzyme B, leading to the induction of target cell apoptosis.
- FasL mechanism (FasL-mechanismus) — cytotoxic activity of NKT lymphocytes mediated via the Fas ligand.
Class and exam questions
They belong to innate immunity, recognize lipid antigens in a complex with the CD1d molecule (rather than peptides with MHC), and possess natural killer features.
They belong to innate immunity, recognize lipid antigens in a complex with the CD1d molecule (rather than peptides with MHC), and possess natural killer features.
In the thymus, they secrete predominantly IL-4. In the periphery, IFNγ production increases, while IL-4 continues to be produced exclusively by the CD4+ subpopulation.
In the thymus, they secrete predominantly IL-4. In the periphery, IFNγ production increases, while IL-4 continues to be produced exclusively by the CD4+ subpopulation.
Positive selection is carried out by cortical double-positive (CD4+CD8+) thymocytes, as they bear the necessary CD1d molecule.
Positive selection is carried out by cortical double-positive (CD4+CD8+) thymocytes, as they bear the necessary CD1d molecule.
What else to study on this topic
- Detailed stages of development (from CD4loCD8lo to mature forms)
- Molecular mechanisms of agonist-dependent selection
- Features of the Vα14/Vα24 receptor
- γδT cells: development and functions (comparison with NKT)
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