Immune receptor involved in self-nonself discrimination. In complex with KLRC1 or KLRC2 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 and non-classical MHC class Ib molecules (  , ). Enables cytotoxic cells to monitor the expression of MHC class I molecules in healthy cells and to tolerate self ( ). Primarily functions as a ligand binding subunit as it lacks the capacity to signal.
KLRD1-KLRC1 acts as an immune inhibitory receptor. Key inhibitory receptor on natural killer (NK) cells that regulates their activation and effector functions ( , ). 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 . 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 . 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 (, ). Upon HLA-E-peptide binding, transmits intracellular signals through KLRC1 immunoreceptor tyrosine-based inhibition motifs (ITIMs) by recruiting INPP5D/SHIP-1 and INPPL1/SHIP-2 tyrosine phosphatases to ITIMs, and ultimately opposing signals transmitted by activating receptors through dephosphorylation of proximal signaling molecules (, ).
KLRD1-KLRC2 acts as an immune activating receptor (, ). On cytotoxic lymphocyte subsets recognizes HLA-E loaded with signal sequence-derived peptides from non-classical MHC class Ib HLA-G molecules, likely playing a role in the generation and effector functions of adaptive NK cells and in maternal-fetal tolerance during pregnancy (, ). Regulates the effector functions of terminally differentiated cytotoxic lymphocyte subsets, and in particular may play a role in adaptive NK cell response to viral infection (, ). Upon HLA-E-peptide binding, transmits intracellular signals via the adapter protein TYROBP/DAP12, triggering the phosphorylation of proximal signaling molecules and cell activation (, ).
(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 . 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 .
Subcellular locations: Cell membrane
Expressed in NK cell subsets (at protein level) ( ). Expressed in memory/effector CD8-positive alpha-beta T cell subsets (at protein level) (, ). Expressed in melanoma-specific cytotoxic T cell clones (at protein level) . Expressed in terminally differentiated cytotoxic gamma-delta T cells (at protein level) . 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) .