Natural Killer Receptors (NKRs)

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.

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.

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.