Natural killer T (NKT)cells are a heterogeneous group ofT cells that share properties of both T cells andnatural killer cells. Many of these cells recognize thenon-polymorphicCD1dmolecule, anantigen-presenting molecule that binds self and foreignlipids andglycolipids. They constitute only approximately 1% of allperipheralbloodT cells.[1] Natural killer T cells should neither be confused withnatural killer cells norkiller T cells (cytotoxic T cells).
The term "NK T cells" was first used in mice to define a subset of T cells that expressed the natural killer (NK) cell-associated marker NK1.1 (CD161). It is now generally accepted that the term "NKT cells" refers toCD1d-restricted T cells, present in mice and humans, some of which coexpress a heavily biased, semi-invariantT-cell receptor and NK cell markers.[2]
NKT cells are a subset of T cells that coexpress an αβ T-cell receptor, but also express a variety of molecular markers that are typically associated with NK cells, such asNK1.1. The best-known NKT cells differ from conventional αβ T cells in that their T-cell receptors are far more limited in diversity ('invariant' or 'type 1' NKT).[3] They and other CD1d-restricted T cells ('type 2' NKT) recognize lipids and glycolipids presented by CD1d molecules, a member of theCD1 family of antigen-presenting molecules, rather thanpeptide-major histocompatibility complexes (MHCs). As such, NKT cells are important in recognizing glycolipids from organisms such asMycobacterium, which causestuberculosis.
NKT cells include both NK1.1+ and NK1.1−, as well as CD4+, CD4−, CD8+ and CD8− cells. Natural killer T cells can share other features with NK cells, as well, such asCD16 andCD56expression andgranzyme production.[4][5]
Invariant natural killer T (iNKT) cells express high levels of and are dependent on the transcriptional regulatorpromyelocytic leukemia zinc finger for their development.[6][7]
Classification of natural killer T cells into three groups has been proposed:[2]
| Type 1 NKT | Type 2 NKT | NKT-like | |
|---|---|---|---|
| Other names | classical NKT invariant NKT (iNKT) Vα14i NKT (mouse) Vα24i NKT (human) | non-classical NKT diverse NKT | NK1.1+ T cells CD3+ CD56+ T cells |
| Restriction | CD1d | CD1d | MHC, other? |
| α-GalCer reactivity | + | - | - |
| T-cell-receptor repertoire | Vα14-Jα18: Vβ8.2, 7, 2 (mouse) Vα24-Jα18: Vβ11 (human) | diverse | diverse |
The best-known subset of CD1d-dependent NKT cells expresses an invariant T-cell receptor(TCR) α chain. These are referred to as type I or invariant NKT cells (iNKT) cells. They are notable for their ability to respond rapidly to danger signals and pro-inflammatory cytokines. Once activated, they engage in effector functions, likeNK transactivation,T cell activation and differentiation,B cell activation,dendritic cell activation andcross-presentation activity, andmacrophage activation.
iNKT cells recognize lipid antigens presented byCD1d, a non-polymorphicmajor histocompatibility complex class I-like antigen presenting molecule. These cells are conserved between humans and mice. The highly conserved TCR is made of Va24-Ja18 paired with Vb11 in humans, which is specific for glycolipid antigens.[8] The best known antigen of iNKT cells isalpha-galactosylceramide (αGalCer), which is a synthetic form of a chemical purified from the deep sea spongeAgelas mauritianus.[9] iNKT cells develop in the thymus, and distribute to the periphery. They are most commonly found in the liver, but are also found in the thymus, spleen, peripheral blood, bone marrow and fat tissue. In comparison to mice, humans have fewer iNKT cells and have a wide variation in the amount of circulating iNKT cells.[8]
Currently, there are five major distinct iNKT cell subsets. These subset cells produce a different set of cytokines once activated. The subtypes iNKT1, iNKT2 and iNKT17 mirrorTh Cell subsets in cytokine production. In addition there are subtypes specialized inT follicular helper-like function andIL-10 dependent regulatory functions.[10] Once activated iNKT cells can impact the type and strength of an immune response. They engage in cross talk with other immune cells, likedendritic cells,neutrophils andlymphocytes.[11] Activation occurs by engagement with their invariant TCR. iNKT cells can also be indirectly activated through cytokine signaling.[8]
While iNKT cells are not very numerous, their unique properties makes them an important regulatory cell that can influence how the immune system develops.[12] They are known to play a role in chronic inflammatory diseases like autoimmune disease, asthma and metabolic syndrome. In human autoimmune diseases, their numbers are decreased in peripheral blood. It is not clear whether this is a cause or effect of the disease. Absence of microbe exposure in early development led to increased iNKT cells and immune morbidity in a mouse model.[13]
Upon activation, NKT cells are able to produce large quantities ofinterferon gamma,IL-4, andgranulocyte-macrophage colony-stimulating factor, as well as multiple othercytokines andchemokines (such asIL-2,IL-13,IL-17,IL-21, andTNF-alpha).
NKT cells recognize protected microbial lipid agents which are presented by CD1d-expressing antigen presenting cells. This serves as a pathway for NKT cells to fight against infections and enhance the humoral immunity. The NKT cells provide support and help to B cells which act as a microbial defense and aid in targeting for B-cell vaccines.[14]
NKT cells seem to be essential for several aspects ofimmunity because their dysfunction or deficiency has been shown to lead to the development ofautoimmune diseases such asdiabetes,autoinflammatory diseases such asatherosclerosis, andcancers. NKT cells have recently been implicated in the disease progression of human asthma.[15]
The clinical potential of NKT cells lies in the rapid release of cytokines (such as IL-2, IFN-gamma, TNF-alpha, and IL-4) that promote or suppress different immune responses.
Most clinical trials with NKT cells have been performed withcytokine-induced killer cells (CIK).[16]
{{cite journal}}: CS1 maint: multiple names: authors list (link)