Natural Killer Receptors (NKRs)

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What are Natural Killer Receptors (NKRs)?

Natural killer receptors (NKRs) generally refer to characterized receptors on the surface natural killer (NK) cells which play a crucial role in the innate immune response by recognizing and lysing the infected and tumor cells. As a subset of effector lymphocytes in the innate immune system, NK cells accurately recognizing infected or transformed cells and exerting effector functions are tightly regulated by a series of activating and inhibiting receptors.

In humans, inhibitory NKRs are mainly encoded by genes in the leukocyte receptor complex (LRC), such as killer immunoglobulin-like receptors (KIRs), most of which interact with major histocompatibility complex (MHC) class I proteins. Activating NKRs are multichain complexes responsible for the induction of NK cell cytotoxicity, mainly including natural cytotoxicity receptors (NCRs, e.g., NKp30, NKp46, NKp44), DNAX accessory molecule 1 (DNAM1, CD226), natural killer group 2D (NKG2D, CD314), etc.

NK cell activation is controlled by the integration of signals from activation and inhibitory receptors. Fig.1 NK cell activation is controlled by the integration of signals from activation and inhibitory receptors. (French, 2003)

γδ T Cell Natural Killer Receptors

γδ T cells are a small group of unusual T lymphocytes characterized by expression of the γδ T cell receptor ((γδ-TCR), serving as important arms in the immune response to infections and tumors. In addition to the featured γδ-TCR, γδ T cells also express a range of co-receptors or costimulatory molecules, which activate and induce various effector functions of γδ T cells. The important co-receptors on the surface of γδ T cell sharing with NK cells mainly include NKG2D, NCRs, DNAM1, and KIRs, by which these γδ T cell NKRs interact with specific ligands and mediate a significant role in the recognition and cytotoxicity on cancer cells. All these receptors and reactive ligands are promising targets for γδ T cell immunotherapy development for cancer treatment.

Receptor–ligand interactions mediating tumor cell recognition by human γδ T cells. Fig.2 Receptor-ligand interactions mediating tumor cell recognition by human γδ T cells. (Silva-Santos, 2015)

Important γδ T Cell Natural Killer Receptors

  • NKG2D

NKG2D, also known as CD314, is a C-type lectin-like receptor expressed on NK cells, Vδ1+ and Vδ2+ T cells, and CD8+ αβ T cells. By binding to MHC I, MHC class I-related chain A (MICA), UL16-binding proteins (ULBPs) expressed on stressed and tumor cells, NKG2D activates γδ T cells to release cytolytic and cytotoxic molecule, such as perforin and granzyme B.

  • NCRs

Currently identified NCRs on the surface of γδ T cells are NKp30 (NCR3, CD337) and NKp44 (NCR2, CD33). In vitro expansion of Vδ1+ γδ T cells, NKp30 and NKp44 have been demonstrated notably up-expressed after stimulated with TCR agonists and cytokines. And the NKp30 and NKp44 up-expressed Vδ1+ γδ T cells had an enhanced capacity of targeting multiple hematological and solid tumors.

  • DNAM1

DNAM1 (CD226), an immunoglobulin superfamily receptor mainly expressed on the surface of NK cells and monocytes, is another activating NKR involved in the activation of Vγ9Vδ2 T cells and tumor cell cytotoxicity. Vγ9Vδ2 T cell DNAM1 reacts with nectin-2 and nectin-like 5 expressed on tumor cells (hepatocellular carcinoma and breast cancer), promotes the activation and cytotoxic activity of Vγ9Vδ2 T cells.


  1. French, A., Yokoyama, W.M. Natural killer cells and autoimmunity. Arthritis Research & Therapy. 2003, 6(1): 8-14.
  2. Silva-Santos, B., et al. γδ T cells in cancer. Nature Reviews Immunology. 2015, 15(11): 683-691.
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