CD314 at a glance

CD314, also known as NKG2D (natural killer receptor G2D) or KLRK1 (killer cell lectin-like receptor subfamily K, member 1), serves to the immune system as a danger sensor. It is a homodimeric C-type lectin-like activating receptor and costimulator with type II membrane orientation (C terminus extracellular). CD314 homodimers are associated with DAP10, a membrane adaptor protein that signals similar to CD28 by recruitment of phosphatidylinositol 3-kinase. CD314 is expressed mainly on cytotoxic T cells and NK cells and upon binding to its ligands, it stimulates cytotoxic reaction against the target cell. On Tc cells, gamma/delta T cells and other CD314 positive T cell subpopulations it works as a costimulatory receptor, on NK cells it is a primary activating receptor. Under particular conditions CD314 can be induced also on some myeloid cells.
Fig-1-alternativa.jpgCD314 ligands of MHC class-I family (MICA, MICB) and of RAET1 family (ULBP1-6) are usually expressed on the surface of stressed cells and their presence there is a signal for immunity reaction against these cells. Exposition of CD314 ligands can be induced e.g. by DNA damage, TLR signaling, viral infection, or under specific cytokine conditions, such as in case of inflammation or autoimmunity. It can be also an important signal of tumor cells, however, some cancers are able to remove CD314 ligands from their surface to evade the immune system. One of possible therapeutic strategies is to restore or increase CD314 ligands on tumor cells by irradiation.
Although CD314 is a stimulatory receptor, in the immune system it can play complex roles. If its ligands appear on antigen presenting cells, it can work as an immunosuppresive factor, if they are present on Treg cells, CD314 can suppress particular immunotolerance mechanism etc. Interestingly, CD314 ligands can be expressed even on NK cells themselves, which seems to represent an inter-NK cell regulatory mechanism.

Fig. 1: A cell suffering from stress (in this case caused by UV light) expresses on its surface CD314 ligands that are detected by CD314 of a cytotoxic cell, which results in its elimination.
The mouse monoclonal antibody 1D11 recognizes an extracellular epitope of human CD314 and can be used for flow cytometry, immunoprecipitation, immunohistochemistry and functional applications. It is able to block CD314 ligand binding. Currently available formats are: purified (11-650-C100), purified azide free (10-650-C100), FITC (1F-650-T100), PE (1P-650-T100), APC (1A-650-T100).
The mouse monoclonal antibody 6D4 recognizes a common extracellular epitope on CD314 ligands  MICA and MICB and can be used for flow cytometry, immunoprecipitation, immunohistochemistry and functional applications. It is able to block CD314-mediated activation of NK cells and cytotoxic T cells. Currently available formats are: purified (11-822-C100), biotin (1B-822-C100), FITC (1F-822-C100), PE (1P-822-C100), APC (1A-822-C100), Alexa Fluor® 647 (A6-822-C100), Alexa Fluor® 700 (A7-822-C100), and PE-Cy™7 (T7-822-C100).
Fig. 2: Separation of human CD314 positive CD56 positive NK cells (red-filled) from CD314 negative CD56 negative lymphocytes (black-dashed) in flow cytometry analysis (surface staining) of human peripheral whole blood stained using anti-human CD314 (1D11) APC antibody.


Further reading:
Lanier L: NKG2D receptor and its ligands in host defense. Cancer Immunol Res. 2015; 3(6):575–582.
Miller JS, Lanier L: Natural killer cells in cancer immunotherapy. Annu Rev Cancer Biol. 2019; 3:77-103.
Babic M, Dimitropoulos C, Hammer Q, Stehle C, Heinrich F, Sarsenbayeva A, Eisele A, Durek P, Mashreghi MF, Lisnic B, Van Snick J, Löhning M, Fillatreau S, Withers DR, Gagliani N, Huber S, Flavell RA, Polic B, Romagnani C: NK cell receptor NKG2D enforces proinflammatory features and pathogenicity of Th1 and Th17 cells. J Exp Med. 2020 Aug 3;217(8):e20190133.
Trembath AP, Markiewicz MA: More than Decoration: Roles for natural killer group 2 member D ligand expression by immune cells. Front Immunol. 2018 Feb 12;9:231.
Baracho GV, Kara N, Rigaud S, Lo E, Widmann SJ, Tyznik AJ: Functional phenotyping of circulating human cytotoxic T cells and NK cells using a 16-color flow cytometry panel. STAR Protoc. 2021 Dec 29;3(1):101069.