KIR3DL2 Human
Description
Genetic Structure
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Chromosomal location: Chromosome 19q13.4 within the leukocyte receptor complex (LRC) .
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Gene length: 16,256 bp genomic sequence, encoding a 1,368 bp cDNA .
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Polymorphism: 62 allelic variants reported, with up to five single amino acid polymorphisms per individual .
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Regulatory elements: Unique RUNX, c-myc, p53, and NFκB transcription factor binding sites influence its expression .
Protein Structure
Cellular Distribution
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NK cells: Expressed in 24.3% of peripheral NK cells (IQR: 18.7–27.7) .
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T cells: Higher expression in CD4+ (5%) and CD8+ (9%) T cells compared to other KIRs .
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Disease-associated cells: Overexpressed in Sézary syndrome (cutaneous T-cell lymphoma) and ankylosing spondylitis .
Ligand Interactions
Immune Regulation
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Inhibitory signaling: Engages HLA class I ligands to suppress NK cell cytotoxicity and T cell effector functions .
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Licensing mechanism: Facilitates NK cell maturation via interactions with self-HLA molecules .
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Crosstalk with TLR9: Enhances pro-inflammatory responses by delivering CpG DNA to endosomal TLR9 .
Pathological Implications
Targeted Therapies
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IPH4102: Humanized anti-KIR3DL2 monoclonal antibody in Phase II trials for cutaneous T-cell lymphomas .
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Diagnostic utility: Flow cytometry antibodies (e.g., clones 539304) enable detection of KIR3DL2+ cells in blood .
Clinical Trial Data
Comparative Analysis With Related KIRs
| Feature | KIR3DL2 | KIR3DL1 | KIR2DL1 |
|---|---|---|---|
| Ligands | HLA-A3/A11, HLA-B27, HLA-F | HLA-Bw4 | HLA-C (w4/w6) |
| Expression | Ubiquitous (framework gene) | Haplotype-dependent | Haplotype-dependent |
| Cytoplasmic domain | Long (ITIM-containing) | Long (ITIM-containing) | Long (ITIM-containing) |
| Disease association | Sézary syndrome, spondylitis | HIV progression | Pregnancy complications |
Research Challenges and Future Directions
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Functional redundancy: Overlap with KIR3DL1 (86% extracellular domain homology) complicates ligand specificity studies .
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Therapeutic resistance: Sézary cells exhibit heterogeneous KIR3DL2 expression post-IPH4102 therapy .
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Primate models: Limited to non-human primates due to absence of structural orthologs in rodents .
Product Specs
Killer Cell Immunoglobulin Like Receptor, Three Ig Domains And Long Cytoplasmic Tail 2, Killer Cell Immunoglobulin-Like Receptor, Three Domains, Long Cytoplasmic Tail, 2, P70 Natural Killer Cell Receptor Clone CL-5, Natural Killer-Associated Transcript 4, CD158 Antigen-Like Family Member K, MHC Class I NK Cell Receptor, P70 NK Receptor CL-5, CD158K, NKAT-4, NKAT4, Killer Cell Immunoglobulin-Like Receptor 3DL2, Killer-Cell Immunoglobulin-Like Receptor, P70 Killer Cell Inhibitory Receptor, Killer Ig Receptor, KIR Antigen 3DL2, CD158k Antigen, KIR-3DL2, NKAT4B, 3DL2, P140.
ADPLMGGQDK PFLSARPSTV VPRGGHVALQ CHYRRGFNNF MLYKEDRSHV PIFHGRIFQE SFIMGPVTPA HAGTYRCRGS RPHSLTGWSA PSNPLVIMVT GNHRKPSLLA HPGPLLKSGE TVILQCWSDV MFEHFFLHRE GISEDPSRLV GQIHDGVSKA NFSIGPLMPV LAGTYRCYGS VPHSPYQLSA PSDPLDIVIT GLYEKPSLSA QPGPTVQAGE NVTLSCSSWS SYDIYHLSRE GEAHERRLRA VPKVNRTFQA DFPLGPATHG GTYRCFGSFR ALPCVWSNSS DPLLVSVTGN PSSSWPSPTE PSSKSGICRH LHVEPKSCDK THTCPPCPAP ELLGGPSVFL FPPKPKDTLM ISRTPEVTCV VVDVSHEDPE VKFNWYVDGV EVHNAKTKPR EEQYNSTYRV VSVLTVLHQD WLNGKEYKCK VSNKALPAPI EKTISKAKGQ PREPQVYTLP PSRDELTKNQ VSLTCLVKGF YPSDIAVEWE SNGQPENNYK TTPPVLDSDG SFFLYSKLTV DKSRWQQGNV FSCSVMHEAL HNHYTQKSLS LSPGKHHHHH H.
Q&A
Frequently Asked Questions (FAQs) for KIR3DL2 Research
Advanced Research Questions
How do conflicting data on KIR3DL2’s role in autoimmunity arise?
Contradictions stem from allelic diversity and ligand availability. For example:
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Pemphigus foliaceus: KIR3DL2001* with HLA-A3/A11 increases risk (OR=3.76), but activating KIRs are protective .
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Experimental variables:
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Resolution strategy: Use CRISPR-edited cell lines to isolate allele-specific effects .
What methodologies address KIR3DL2’s dual roles in cancer immunity?
KIR3DL2 exhibits context-dependent roles:
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Pro-tumor: In Sézary syndrome, KIR3DL2+ T cells evade immune surveillance .
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Anti-tumor: Blocking KIR3DL2 enhances NK-mediated lysis of HHLA2+ tumors .
Experimental workflows:
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Humanized mouse models: Transplant HHLA2+ tumors into NSG mice with KIR3DL2+ NK cells .
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Therapeutic blockade: Anti-KIR3DL2 mAbs (e.g., B5B5) tested in phase I trials .
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Single-cell RNA-seq: Profile KIR3DL2+ tumor-infiltrating lymphocytes to identify co-inhibitory receptors .
How does KIR3DL2 differentiate self-DNA from pathogen-derived DNA?
KIR3DL2 preferentially internalizes CpG motifs from pathogens (e.g., parasitic worms) over human DNA. Methods to study this:
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Genomic analysis: Compare CpG-flanking sequences in human vs. pathogen genomes (e.g., Schistosoma) .
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Functional assays:
| CpG Source | Uptake Efficiency (%) | IFN-γ Increase (vs. control) | Citation |
|---|---|---|---|
| Human genome | 12 ± 3 | 1.2-fold | |
| Schistosoma spp. | 78 ± 9 | 4.5-fold |
What are unresolved controversies in KIR3DL2 signaling pathways?
Key debates include:
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Inhibitory vs. activating signals: While most studies report inhibition via ITIM domains, CpG-DNA binding paradoxically activates TLR9 .
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Ligand redundancy: HLA-B27 free heavy chains bind KIR3DL2, but their physiological relevance remains unclear .
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Therapeutic targeting: Blocking KIR3DL2 may benefit Sézary syndrome but risks exacerbating autoimmune conditions .
Recommended approaches:
Product Science Overview
Killer Cell Immunoglobulin-Like Receptors (KIRs) are a family of receptors expressed on the surface of natural killer (NK) cells and some T-cell subsets. These receptors play a crucial role in the regulation of the immune response by interacting with major histocompatibility complex (MHC) class I molecules. Among these receptors, the Killer Cell Immunoglobulin-Like Receptor, 3 Domains Long Cytoplasmic Tail 2 (KIR3DL2) is of particular interest due to its unique structure and function.
KIR3DL2 is characterized by its three immunoglobulin-like domains, designated as D0, D1, and D2 . These domains are sequentially arranged and contribute to the receptor’s ability to bind to its ligands. The receptor also includes a signal peptide, a stem region, a transmembrane region, and a long cytoplasmic tail . The cytoplasmic tail contains immunoreceptor tyrosine-based inhibitory motifs (ITIMs), which are essential for transmitting inhibitory signals within the cell .
The KIR3DL2 gene is located on chromosome 19q13.4 and is part of the KIR gene cluster . This gene cluster is known for its high degree of polymorphism, which contributes to the diversity of the immune response among individuals. KIR3DL2 is expressed primarily on NK cells and some T-cell subsets . The expression of KIR3DL2 can be regulated by various factors, including DNA methylation and the presence of specific transcription factors .
KIR3DL2 plays a critical role in the immune system by regulating the activity of NK cells. It interacts with MHC class I molecules on the surface of target cells, transmitting inhibitory signals that prevent the NK cells from killing normal, healthy cells . This mechanism is essential for maintaining self-tolerance and preventing autoimmune reactions. Additionally, KIR3DL2 has been implicated in the recognition and elimination of infected or transformed cells, contributing to the body’s defense against infections and cancer .
Recombinant KIR3DL2 is produced using the Sf9 insect cell expression system. This system is commonly used for the production of recombinant proteins due to its ability to perform post-translational modifications similar to those in mammalian cells. The recombinant KIR3DL2 protein retains the functional properties of the native receptor, making it a valuable tool for research and therapeutic applications.
Recombinant KIR3DL2 has several applications in biomedical research and clinical practice. It can be used to study the interactions between KIRs and MHC class I molecules, providing insights into the mechanisms of immune regulation. Additionally, recombinant KIR3DL2 can be employed in the development of novel immunotherapies for cancer and infectious diseases. By modulating the activity of NK cells, these therapies have the potential to enhance the immune response against tumors and pathogens.
