Killer cell lectin-like receptor subfamily C member 2 (NKG2C) (NKG2C)

Killer cell lectin-like receptor subfamily C member 2 (NKG2C) is an activating receptor primarily expressed on Natural Killer (NK) cells and a subset of CD8+ T cells [1]. It functions as a heterodimer with CD94 to recognize the non-classical MHC class I molecule HLA-E, which presents peptides derived from the leader sequences of other MHC class I molecules or viral proteins [2]. Upon binding to HLA-E, NKG2C signals through the adapter molecule DAP12 (TYROBP), leading to NK cell activation, proliferation, and the release of cytotoxic granules and pro-inflammatory cytokines like IFN-gamma [1,3]. NKG2C is a hallmark of 'adaptive' or 'memory-like' NK cells that expand significantly in response to Human Cytomegalovirus (HCMV) infection and provide enhanced protection against subsequent challenges [4]. In oncology, NKG2C is being explored as a therapeutic target to enhance NK cell-mediated anti-tumor immunity, particularly through the use of bispecific engagers and CAR-NK cells that specifically activate NKG2C+ populations [5]. The therapeutic strategy often involves balancing NKG2C activation with the inhibition of its counterpart, NKG2A, to overcome immune evasion by tumors expressing HLA-E [6]. Beyond cancer, NKG2C-positive cells are studied for their role in controlling various viral infections, including HIV and COVID-19, where they contribute to a more robust immune response [4]. (Citations: [1] UniProt P26717; [2] Braud VM, et al. Nature 1998; [3] Lanier LL. Annu Rev Immunol 2005; [4] Gumá M, et al. Blood 2004; [5] Schiavoni G, et al. Front Immunol 2022; [6] Borst L, et al. Front Immunol 2020).

Other names

KLRC2CD159cNKG2-CCD94/NKG2C receptor complexKiller cell lectin-like receptor subfamily C, member 2

Agonism of the NKG2C receptor, typically as a heterodimer with CD94, to trigger NK cell-mediated cytotoxicity and cytokine production (e.g., IFN-gamma) against cells expressing the non-classical MHC class I molecule HLA-E.