Details for: KIR2DL1

Gene ID: 3802

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: KIR2DL1

Ensembl ID: ENSG00000125498

Description: killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • activated type II NK T cell CL0000931
    CSI 19.49
    rCSI 21.93%
    PRS 97.32
  • CD16-positive, CD56-dim natural killer cell, human CL0000939
    CSI 9.1
    rCSI 6.07%
    PRS 96.29
  • decidual natural killer cell, human CL0002343
    CSI 2.21
    rCSI 22.49%
    PRS 95.99
  • effector memory CD8-positive, alpha-beta T cell, terminally differentiated CL0001062
    CSI 0.32
    rCSI 1.6%
    PRS 97.49

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

Comma-separated if multiple.
Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

Loading network (please wait)...

Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [KIR2DL1](/details-gene/3802) (Killer Cell Immunoglobulin Like Receptor, Two Ig Domains And Long Cytoplasmic Tail 1) is a protein-coding gene located on chromosome 19. It encodes a transmembrane glycoprotein that functions as an inhibitory receptor on the surface of specific immune cells, most notably [natural killer (NK) cells](/details-cell/CL0000623). As a member of the KIR family, [KIR2DL1](/details-gene/3802) plays a crucial role in regulating the cytotoxic activity of NK cells by recognizing specific human leukocyte antigen (HLA) class I allotypes, particularly HLA-C, on potential target cells ([Link](https://doi.org/10.1126/science.7716543)). This interaction prevents the killing of healthy "self" cells, a fundamental process in immune self-tolerance. The expression data strongly supports its central role in NK cell biology, with the gene showing highly significant and specific expression in various NK cell subsets, including [activated type II NK T cells](/details-cell/CL0000931) and [CD16-positive, CD56-dim natural killer cells, human](/details-cell/CL0000939). ## Cellular Roles and Expression Landscape The expression profile of [KIR2DL1](/details-gene/3802) underscores its specialized function within the innate and adaptive immune systems, primarily as a key regulator of NK cell function. **Overall**, the gene's significance is most pronounced in cell types central to cytotoxic immunity. The highest significance is observed in [activated type II NK T cells](/details-cell/CL0000931) (CSI: 19.49), a population with characteristics of both T and NK cells, suggesting [KIR2DL1](/details-gene/3802) is a defining feature of their regulatory machinery. Its high significance in mature, cytotoxic [CD16-positive, CD56-dim natural killer cells, human](/details-cell/CL0000939) (CSI: 9.10) is consistent with its canonical role in preventing NK-mediated attacks on healthy tissues. Furthermore, its notable presence in [decidual natural killer cells, human](/details-cell/CL0002343) (CSI: 2.21) points towards a specialized role in maternal-fetal tolerance during pregnancy. A lower but still notable significance is found in [effector memory CD8-positive, alpha-beta T cells, terminally differentiated](/details-cell/CL0001062) (CSI: 0.32). This suggests that in addition to its primary role in the innate immune system, [KIR2DL1](/details-gene/3802) may also be expressed on a subset of highly differentiated adaptive lymphocytes, where it could contribute to modulating T cell responses during chronic antigen exposure. ## Pathways and Molecular Function The molecular functions of [KIR2DL1](/details-gene/3802) are directly tied to its role as a cell surface inhibitory receptor. Functional annotations place it within the [plasma membrane](/details-cell/GO:0005886) where it acts as a [signaling receptor](/details-cell/GO:0038023). Its engagement with specific HLA-C ligands on other cells initiates the [Natural killer cell inhibitory signaling pathway](/details-cell/GO:0002769), a critical component of the broader [immune response](/details-cell/GO:0006955). This inhibitory signal is central to the Reactome pathway for [Immunoregulatory interactions between a lymphoid and a non-lymphoid cell](/details-cell/R-HSA-198933). Upon binding its ligand, the long cytoplasmic tail of [KIR2DL1](/details-gene/3802) becomes phosphorylated, recruiting protein phosphatases that counteract activating signals within the NK cell. This mechanism ensures that NK cells remain quiescent towards healthy cells expressing appropriate "self" MHC molecules, thereby contributing to the regulation of the [adaptive immune system](/details-cell/R-HSA-1280218) and overall immune homeostasis ([Link](https://doi.org/10.1038/ni.1635)). ## Research Directions The function of [KIR2DL1](/details-gene/3802) as an inhibitory checkpoint on NK cells makes it a gene of significant interest in oncology and infectious disease research. Its ability to suppress cytotoxic cell activity can be co-opted by diseased cells to evade immune surveillance. **Proposed Hypotheses:** 1. Tumor cells that upregulate specific HLA-C allotypes recognized by [KIR2DL1](/details-gene/3802) can effectively "turn off" patrolling NK cells, representing a key mechanism of immune evasion. The expression level of the cognate HLA-C ligand on a tumor may therefore be a predictive biomarker for patient response to NK cell-based immunotherapies. 2. The expression of [KIR2DL1](/details-gene/3802) on terminally differentiated [effector memory CD8-positive, alpha-beta T cells](/details-cell/CL0001062) may contribute to a state of functional exhaustion in chronic viral infections (e.g., HIV, CMV) or within the tumor microenvironment. In this context, [KIR2DL1](/details-gene/3802) could act as an additional inhibitory checkpoint, similar to PD-1 or CTLA-4, limiting the efficacy of these T cells. **Experimental Approach:** To test the first hypothesis, one could employ a co-culture assay. A panel of tumor cell lines (e.g., from melanoma or lung cancer) could be genetically engineered using CRISPR-Cas9 to either knock out all HLA-C expression or to specifically express a known [KIR2DL1](/details-gene/3802) ligand (e.g., HLA-Cw4). These engineered tumor cells would then be co-cultured with primary human NK cells isolated from a donor genotyped for [KIR2DL1](/details-gene/3802) expression. The functional consequences would be measured by quantifying NK cell degranulation (via surface CD107a staining), intracellular cytokine production (IFN-γ), and tumor cell lysis (using a chromium-51 release assay or similar method). A significant reduction in all three readouts in the presence of the HLA-C ligand would validate the hypothesis that this axis facilitates immune escape. **Therapeutic Potential:** [KIR2DL1](/details-gene/3802) is a prime therapeutic target for cancer immunotherapy. As an inhibitory receptor, the goal would be **inhibition** to block its function and "release the brakes" on NK cells, enhancing their anti-tumor activity. Monoclonal antibodies designed to bind [KIR2DL1](/details-gene/3802) and prevent its interaction with HLA-C are a promising strategy. This approach, known as NK cell checkpoint blockade, could be particularly effective in combination with other immunotherapies that target T cells or with antibody-dependent cell-mediated cytotoxicity (ADCC)-inducing antibodies, thereby leveraging the full potential of the innate cytotoxic immune system.

Genular Protein ID: 683940605

Symbol: KI2L1_HUMAN

Name: CD158 antigen-like family member A

UniProtKB Accession Codes:

P43626 O43470 Q32WE6 Q6H2H3 Q6IST4

Database IDs:

ABCD 1 AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 ChEMBL 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 66 Ensembl 29 EvolutionaryTrace 1 ExpressionAtlas 1 GO 5 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 5 KEGG 1 MANE-Select 1 MIM 1 MINT 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 2 PDBsum 2 PIR 1 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 RNAct 1 Reactome 1 RefSeq 1 SMART 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 7716543

Title: Cloning of immunoglobulin-superfamily members associated with HLA-C and HLA-B recognition by human natural killer cells.

PubMed ID: 7716543

DOI: 10.1126/science.7716543

PubMed ID: 7749980

Title: Molecular clones of the p58 NK cell receptor reveal immunoglobulin-related molecules with diversity in both the extra- and intracellular domains.

PubMed ID: 7749980

DOI: 10.1016/1074-7613(95)90025-x

PubMed ID: 9430221

Title: Human diversity in killer cell inhibitory receptor genes.

PubMed ID: 9430221

DOI: 10.1016/s1074-7613(00)80394-5

PubMed ID: 14607943

Title: Activation of a subset of human NK cells upon contact with Plasmodium falciparum-infected erythrocytes.

PubMed ID: 14607943

DOI: 10.4049/jimmunol.171.10.5396

PubMed ID: 23394822

Title: Recombinant structures expand and contract inter and intragenic diversification at the KIR locus.

PubMed ID: 23394822

DOI: 10.1186/1471-2164-14-89

PubMed ID: 24989671

Title: Characterization of a weakly expressed KIR2DL1 variant reveals a novel upstream promoter that controls KIR expression.

PubMed ID: 24989671

DOI: 10.1038/gene.2014.34

PubMed ID: 15057824

Title: The DNA sequence and biology of human chromosome 19.

PubMed ID: 15057824

DOI: 10.1038/nature02399

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 18624290

Title: Evidence that the KIR2DS5 gene codes for a surface receptor triggering natural killer cell function.

PubMed ID: 18624290

DOI: 10.1002/eji.200838434

PubMed ID: 18604210

Title: An essential function for beta-arrestin 2 in the inhibitory signaling of natural killer cells.

PubMed ID: 18604210

DOI: 10.1038/ni.1635

PubMed ID: 9288975

Title: Structure of the inhibitory receptor for human natural killer cells resembles haematopoietic receptors.

PubMed ID: 9288975

DOI: 10.1038/38028

Sequence Information:

  • Length: 348
  • Mass: 38580
  • Checksum: 24F03F14976614EB
  • Sequence:
    • MSLLVVSMAC VGFFLLQGAW PHEGVHRKPS LLAHPGRLVK SEETVILQCW SDVMFEHFLL 
HREGMFNDTL RLIGEHHDGV SKANFSISRM TQDLAGTYRC YGSVTHSPYQ VSAPSDPLDI 
VIIGLYEKPS LSAQLGPTVL AGENVTLSCS SRSSYDMYHL SREGEAHERR LPAGPKVNGT 
FQADFPLGPA THGGTYRCFG SFHDSPYEWS KSSDPLLVSV TGNPSNSWPS PTEPSSKTGN 
PRHLHILIGT SVVIILFILL FFLLHRWCSN KKNAAVMDQE SAGNRTANSE DSDEQDPQEV 
TYTQLNHCVF TQRKITRPSQ RPKTPPTDII VYTELPNAES RSKVVSCP

Genular Protein ID: 3389585811

Symbol: Q6H2H2_HUMAN

Name: N/A

UniProtKB Accession Codes:

Q6H2H2 A0A1W2PPV9

Database IDs:

ARBA 3 BioGRID-ORCS 1 CDD 1 CTD 1 DNASU 1 DisGeNET 1 EMBL 36 Ensembl 5 GO 1 Gene3D 1 HGNC 1 InterPro 5 KEGG 1 NCBI Taxonomy 1 OrthoDB 1 PANTHER 2 Pfam 1 PharmGKB 1 Proteomes 2 RefSeq 1 SAM 3 SMART 2 SUPFAM 1 UCSC 1

Citations:

PubMed ID: 14607943

Title: Activation of a subset of human NK cells upon contact with Plasmodium falciparum-infected erythrocytes.

PubMed ID: 14607943

Sequence Information:

  • Length: 348
  • Mass: 38534
  • Checksum: 3B4B2C086F63650E
  • Sequence:
    • MSLLVVSMAC VGFFLLQGAW PHEGVHRKPS LLAHPGRLVK SEETVILQCW SDVMFEHFLL 
HREGMFNDTL RLIGEHHDGV SKANFSISRM TQDLAGTYRC YGSVTHSPYQ VSAPSDPLDI 
VIIGLYEKPS LSAQPGPTVL AGENVTLSCS SRSSYDMYHL SREGEAHERR LPAGTKVNGT 
FQANFPLGPA THGGTYRCFG SFRDSPYEWS KSSDPLLVSV TGNPSNSWPS PTEPSSETGN 
PRHLHILIGT SVVIILFILL FFLLHCWCSN KKNAAVMDQE SAGNRTANSE DSDEQDPQEV 
TYTQLNHCVF TQRKITRPSQ RPKTPPTDII VYTELPNAES RSKVVSCP