Immune inhibitory receptor involved in self-nonself discrimination. In complex with KLRD1 on cytotoxic and regulatory lymphocyte subsets, recognizes non-classical major histocompatibility (MHC) class Ib molecule HLA-E loaded with self-peptides derived from the signal sequence of classical MHC class Ia molecules. Enables cytotoxic cells to monitor the expression of MHC class I molecules in healthy cells and to tolerate self (PubMed:9486650, PubMed:18083576, PubMed:9430220). Upon HLA-E-peptide binding, transmits intracellular signals through two immunoreceptor tyrosine-based inhibition motifs (ITIMs) by recruiting INPP5D/SHP-1 and INPPL1/SHP-2 tyrosine phosphatases to ITIMs, and ultimately opposing signals transmitted by activating receptors through dephosphorylation of proximal signaling molecules (PubMed:9485206, PubMed:12165520). Key inhibitory receptor on natural killer (NK) cells that regulates their activation and effector functions (PubMed:9486650, PubMed:9430220, PubMed:9485206, PubMed:30860984). Dominantly counteracts T cell receptor signaling on a subset of memory/effector CD8-positive T cells as part of an antigen-driven response to avoid autoimmunity (PubMed:12387742). On intraepithelial CD8-positive gamma-delta regulatory T cells triggers TGFB1 secretion, which in turn limits the cytotoxic programming of intraepithelial CD8-positive alpha-beta T cells, distinguishing harmless from pathogenic antigens (PubMed:18064301). In HLA-E-rich tumor microenvironment, acts as an immune inhibitory checkpoint and may contribute to progressive loss of effector functions of NK cells and tumor-specific T cells, a state known as cell exhaustion (PubMed:30503213, PubMed:30860984). (Microbial infection) Viruses like human cytomegalovirus have evolved an escape mechanism whereby virus-induced down-regulation of host MHC class I molecules is coupled to the binding of viral peptides to HLA-E, restoring HLA-E expression and inducing HLA-E-dependent NK cell immune tolerance to infected cells. Recognizes HLA-E in complex with human cytomegalovirus UL40-derived peptide (VMAPRTLIL) and inhibits NK cell cytotoxicity. (Microbial infection) May recognize HLA-E in complex with HIV-1 gag/Capsid protein p24-derived peptide (AISPRTLNA) on infected cells and may inhibit NK cell cytotoxicity, a mechanism that allows HIV-1 to escape immune recognition. (Microbial infection) Upon SARS-CoV-2 infection, may contribute to functional exhaustion of cytotoxic NK cells and CD8-positive T cells (PubMed:32203188, PubMed:32859121). On NK cells, may recognize HLA-E in complex with SARS-CoV-2 S/Spike protein S1-derived peptide (LQPRTFLL) expressed on the surface of lung epithelial cells, inducing NK cell exhaustion and dampening antiviral immune surveillance (PubMed:32859121). Heterodimer with KLRD1; disulfide-linked (PubMed:18083576, PubMed:18332182, PubMed:18448674). KLRD1-KLRC1 heterodimer interacts with peptide-bound HLA-E-B2M heterotrimeric complex (PubMed:18083576). Competes with KLRC2 for its interaction with HLA-E (PubMed:18083576). Interacts (via ITIM) with INPP5D/SHIP-1 and INPPL1/SHIP-2 (via SH2 domain). Predominantly expressed in NK cells (at protein level) (PubMed:9430220, PubMed:9485206, PubMed:20952657). Expressed in intraepithelial CD8-positive T cell subsets with higher frequency in gamma-delta T cells than alpha-beta T cells (at protein level) (PubMed:18064301). Expressed in memory gamma-delta T cells (at protein level) (PubMed:20952657). Restricted to a subset of memory/effector CD8-positive alpha-beta T cells (at protein level) (PubMed:12387742). Expressed in intratumoral NK and CD8-positive T cells (PubMed:30503213). Expressed in melanoma-specific cytotoxic T cell clones (at protein level) (PubMed:9485206). KLRD1-KLRC1 and KLRD1-KLRC2 are differentially expressed in NK and T cell populations, with only minor subsets expressing both receptor complexes (at protein level) (PubMed:20952657). Up-regulated in memory CD8-positive alpha-beta T cell clones upon antigen-specific stimulation. The cytosolic N-terminus contains two immunoreceptor tyrosine-based inhibitory motifs (ITIMs), which are essential for the association with INPP5D/SHIP-1 and INPPL1/SHIP-2 phosphatases and functional inhibition. Phosphorylated. NKG-2A