Originating from the thymus, NKT (Natural Killer T) cells represent a combination of T cell and NK cell attributes/markers. They express a T cell receptor (TCR) complex and several NK cell markers. The ability of these cells to produce Th1 and Th2-related cytokines has implicated them in several fields, including transplantation, tumors, autoimmunity, and allergy.

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Classification

 

While NKTs display a TCR, the chains displayed are often very limited. This group of NKTs has thus been aptly named invariant NKT cells (iNKT). iNKT cells mostly express the Vα14-Jα18 α chain with a variable Vβ2, Vβ7, or Vβ8.2 chain in mice, while human iNKT cells tend to express Vα24-Jα18/Vβ11. While the iNKTs are the most well-understood class, there are others with semi-variant TCRs or NKT-like features. Some NKT cells express CD4+ or CD8+ individually. Others still are double negative (CD4-, CD8-).
 

  Type I cells(Classical NKTs) Type II cells(Non-classical NKTs) NKT-like cells
CD1d dependent Yes Yes No
α-GalCer reactive Yes No No
TCRα chain Vα14-Jα18 (mice); Vα24-Jα18 (humans) Diverse, but some Vα3.2-Jα 9, Vα8 (mice) Diverse
TCRβ chain Vβ2, Vβ7, and Vβ8.2 (mice); Vβ11 (humans) Diverse, but some Vβ8.2 (mice) Diverse
NK1.1 or (CD161) Positive (resting mature); negative/low (immature or post-activation) Positive and negative Positive
Subsets CD4+, DN (mice); CD4+, CD8+, DN (humans) CD4+ and DN (mice) CD4+, CD8+, and DN
IL-4 production Yes Yes No
IFN-γ production Yes Yes Yes

DN: Double Negative (CD4-CD8-); Adapted from Godfrey, D. et al. 2004. Nat. Rev. Immunol. 4:231.

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CD1d Restriction

 

Unlike classical T cells, NKT cells are activated by CD1d and not MHCs. While classical T cells recognize MHC-presented peptides, NKT cells recognize lipids/glycolipids. One of the most famous NKT ligands is called α-galactosylceramide (αGalCer). Originally derived from sea sponges, this compound was found to effectively activate NKT cells. αGalCer also shares structural similarities with components in bacterial cell walls. As such, NKT cells can be potent fighters against bacterial infection.

NKT cells will reciprocally activate its antigen presenting cell upon lipid/glycolipid presentation. Once mature, NKT cells produce massive amounts of IFN-γ. Unique among lymphocytes, they are also capable of explosively releasing IL-4 and IL-13 (Th2-related cytokines). NKT cells burn up fast, downregulating their TCR following activation, and undergoing massive apoptosis once the threat has passed. NKT cell numbers remain deflated until new NKT cells emigrate from the thymus. Because of its ability to promote Th2 cells, NKTs been implicated in Type 1 Diabetes and Asthma.
 

Structure for αGalCer , a popular ligand of NKT cells.

 

References:
Bendelac, A. et al. 2007. Ann. Rev. Immunol. 25:336.

 

Development

 

Like T cells, NKT cells begin their training and development in the thymus. At the double positive (CD4+CD8+) stage, they begin to diverge, undergoing several rounds of division and even acquiring a memory/effector-like phenotype just before they shuttle out of the thymus. NKT cells will then begin to express NK lineage receptors once it heads to its target tissue.

This adaptation from Bendelac, A. et al. 2007. Ann. Rev. Immunol. 25:336 represents mouse NKT cell development.
DN: Double Negative (CD4-, CD8-) T Cell; DP: Double Positive (CD4+, CD8+) T Cell

tbetNFKBCD44 NK1.1 IL-4 IFN-GCD1D CD4 CD4 CD4 CD4 CD4 CD4 CD8 CD24 CD24 CD24 CD69 CD150SLAM FYN IL4 IL4 MHCI MHCII NFKB NK11 NK11 RORGT PKCT tbet TCR CD44 CD44 IFNG

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