Disease relevance of KIR2DL2

• Similarly, interactions of KIR2DL2 or KIR2DL3 (KIR2DL2/3) with HLA-Cw3-related allotypes on melanomas resulted in decreased tumor cell lysis [1].
• In individuals with HIV-1 viremia, there was a direct correlation between the level of expression of p58.1, p58.2, and CD94 receptors and plasma HIV viremia, suggesting that ongoing active HIV replication has an effect on the expression of such receptors on NK cells [2].
• Identification of the malignant cells in Sézary syndrome cannot be achieved by T-cell clonality studies or by TCR Vbeta monoclonal antibody (mAb) analysis alone; it also relies on CD158k phenotyping [3].

High impact information on KIR2DL2

• Most contacts in the complex are between KIR and conserved HLA-C residues, but a hydrogen bond between Lys 44 of KIR2DL2 and Asn 80 of Cw3 confers the allotype specificity [4].
• In particular, we show here with KIR tetramers that activating KIR2DS2 does not bind HLA-Cw3 molecules recognized by inhibitory KIR2DL2, despite 99% extracellular amino acid identity [5].
• The hinge angle of KIR2DL2 is approximately 80 degrees, 14 degrees larger than that observed in KIR2DL1 despite the existence of conserved hydrophobic residues near the hinge region [6].
• We studied how KIR2DL2 regulates T-cell function [7].
• Gene array studies documented that the inhibition of late signaling events by KIR2DL2 affected transcriptional gene activation [7].

Biological context of KIR2DL2

• Surprisingly, another KIR2D (KIR2DL2), which inhibits NK lysis of cells expressing HLA-C molecules with serine 77 and asparagine 80, bound to HLA-C allotypes carrying either amino acid motif [8].
• Consequently, KIR2DL2 engagement did not inhibit the phosphorylation of early signaling proteins and T-cell-receptor (TCR)-mediated cytotoxicity or granule exocytosis [7].
• RESULTS: Twelve patients with scleroderma, compared with only 2 blood donors, had KIR phenotypes characterized by the presence of the activating KIR2DS2 and the absence of the corresponding inactivating KIR2DL2 (P = 0.005) [9].
• Most KIR2DL2/3 alleles possess an arginine at position 41 (R41), and we predicted through molecular modeling and demonstrated by mutagenesis that R41 most likely interacts with the nearby residues Y77 and D47 [10].

Anatomical context of KIR2DL2

• In contrast, one or both allelic forms of KIR2DL2/KIR2DL3 were expressed by a high proportion of NK cells in all 73 individuals [11].
• Here, we report a significant increased frequency of the more inhibitory AB killer cell immunoglobulin-like receptor (KIR) phenotype in leukemic patients compared to the controls (31.1% in healthy controls vs 51.0% in leukemic patients, Pc=0.002), which is related to the high prevalence of the inhibitory KIR2DL2 in this population (Pc=0.007) [12].
• The expression of p58.2 by CD3(+)CD56(+) TILs and CD94 by NK TILs was also decreased compared to that of hepatic lymphocytes of the control subjects (16.9% vs 73.1%, P = 0.047; 21% vs 49.95%, P = 0.037, respectively) [13].
• We previously reported that CD158k expression delineates Sézary syndrome malignant cells, and, more recently, we identified vimentin at the surface membranes of Sézary cells and normal activated lymphocytes [3].
• To analyze the requirement of p56(lck) kinase in the function of killer inhibitory receptors, we transfected the p56(lck) negative YT-Indy cell line with the cl43 gene encoding for KIR2DL2 [14].

Associations of KIR2DL2 with chemical compounds

• Surprisingly, exchanging the methionine at position 44 in cl42 with the lysine at position 44 in cl43 was sufficient to switch the specificity of cl42 from HLA-Cw*0401 to HLA-Cw*0304, and vice versa [15].

Physical interactions of KIR2DL2

• In our study, a KIR CD3zeta fusion-binding assay did not detect any interaction between the KIR2DL2*004 extracellular domain and several putative KIR2DL2/3 ligands [10].

Other interactions of KIR2DL2

• One of these receptors (KIR2DS2) is closely related in sequence to KIR2DL2 [8].
• Human natural killer cells with polyclonal lectin and immunoglobulinlike receptors develop from single hematopoietic stem cells with preferential expression of NKG2A and KIR2DL2/L3/S2 [16].
• In this work, we analyzed the crystal structure of the ectodomain of FcalphaRI and examined structure similarities between FcalphaRI and KIR2DL1, KIR2DL2 and LIR-1 [17].
• Polymorphic expression of CD158k/p140/KIR3DL2 in Sézary patients [18].
• The p58(+) T cells expressed p58.2 receptor and corresponded to CD3(+), CD8(+), T-cell receptor (TCR) alpha/beta(+) T cells that were CD56(+) and CD28(-) [19].

Analytical, diagnostic and therapeutic context of KIR2DL2

• As YT-Indy-cl43 did not express detectable levels of p56(lck), these results indicate that this kinase is not required for transmitting the negative signals generated by KIR2DL2 ligation [14].

References