Disease relevance of KLRD1

• Imprint of human cytomegalovirus infection on the NK cell receptor repertoire [1].
• Also, these CD94-expressing cells prevented the growth of K562 leukemic cells and CW2 colon cancer cells in NOD/SCID mice in vivo [2].
• Functional modulation of expanded CD8+ synovial fluid T cells by NK cell receptor expression in HLA-B27-associated reactive arthritis [3].
• CD94 and NKG2 are members of the NK cell receptor families, and are encoded in the natural killer gene complex (NKC) on human chromosome 12p12-13, one of the candidate chromosomal regions for rheumatic diseases [4].
• IFN-gamma protects short-term ovarian carcinoma cell lines from CTL lysis via a CD94/NKG2A-dependent mechanism [5].

High impact information on KLRD1

• Because Qa-1 also binds to self Qdm peptides that trigger NK (CD94/ NKG2) receptors on CD8(+) T cells, the machinery for homeostatic regulation of regulatory CD8(+) T cells can be envisioned [6].
• HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C [7].
• The fact that a very small subset of NK cells (approximately equal to 10%) as well as some NK clones (JT11) does not express CD2 argues against a potential role for CD2 as the NK cell receptor [8].
• However, the function and ligand(s) of the NK cell gene complex-encoded human NK cell receptor NKp80 remain elusive [9].
• The structures of activating and inhibitory NK cell surface receptors and their complexes with the ligands determined to date, including killer immunoglobulin-like receptors (KIRs) and their complexes with HLA molecules, CD94, Ly49A, and its complex with H-2Dd, and NKG2D receptors and their complexes with class I MHC homologs, are reviewed here [10].

Biological context of KLRD1

• Human cytomegalovirus (HCMV) infection as well as the HLA-E and killer immunoglobulin-like receptor (KIR) genotypes were considered as potentially relevant variables associated with CD94/NKG2C expression [1].
• Thus, the mechanisms that control cell surface homeostasis of CD94/NKG2A are independent of functional signaling [11].
• Moreover, we transferred the activating function by transfection of the heterologous RBL cell line with CD94/NKG2-C/DAP12 [12].
• We selected two yeast artificial chromosome clones comprising approximately 1.5 Mb of the NK gene complex and established a contig of underlying P1-derived artificial chromosome clones containing all NKG2 and the CD94 genes [13].
• Recognition of human histocompatibility leukocyte antigen (HLA)-E complexed with HLA class I signal sequence-derived peptides by CD94/NKG2 confers protection from natural killer cell-mediated lysis [14].

Anatomical context of KLRD1

• A subset of HLA class I alleles has been shown to inhibit killing by CD94/NKG2A+ NK-cell clones [7].
• It interacts with CD94/NKG2 receptors expressed on the surface of natural killer (NK) cells and T cell subsets [15].
• On the other hand, the CD94-expressing cells have low responsiveness to alloantigen in mixed lymphocyte culture (MLC) and have high transforming growth factor (TGF)-beta1- but low IL-2- producing capacity [2].
• These expanded and purified CD94-expressing cells attacked various malignant cell lines, including solid cancer cell lines, as well as the patients' leukemic cells but not autologous and allogeneic phytohemagglutinin (PHA) blasts in vitro [2].
• Taken together the data support that the interaction of CD94/NKG2C with HCMV-infected fibroblasts, concomitant to the inhibition of human leukocyte antigen (HLA) class I expression, promotes an outgrowth of CD94/NKG2C(+) NK cells [16].

Associations of KLRD1 with chemical compounds

• Confocal microscopy was used to determine whether SH2 domain-bearing tyrosine phosphatase-1 and CD94/NKG2A colocalized intracellularly after receptor ligation [17].
• Molecular characterization of human CD94: a type II membrane glycoprotein related to the C-type lectin superfamily [18].
• Prostaglandin E2 induces the expression of functional inhibitory CD94/NKG2A receptors in human CD8+ T lymphocytes by a cAMP-dependent protein kinase A type I pathway [19].
• Interestingly, when low concentrations of PGE2 or 8-CPT-cAMP were present during the culture, the proportion of CD8+ T cells expressing CD94/NKG2A was two- to five-fold higher [19].
• Conversely, CHX blocked CD94 mRNA expression in PMA-stimulated cells, demonstrating that this process is dependent on new protein synthesis [20].

Physical interactions of KLRD1

• This complex triggered cytotoxicity very efficiently over a wide range of peptide concentrations, suggesting that the HLA-E/G-nonamer complex interacts with the CD94/NKG2 triggering receptor with a significantly higher affinity [21].
• These HLA-G tetramers failed to bind to NK cells and cells transfected with CD94/NKG2 and killer immunoglobulin-like NK receptors [22].
• The CD94/NKG2 C-type lectin receptor complex: involvement in NK cell-mediated recognition of HLA class I molecules [23].

Regulatory relationships of KLRD1

• HLA-E is expressed on trophoblast and interacts with CD94/NKG2 receptors on decidual NK cells [24].
• Specific engagement of the KLR triggered cytotoxicity and cytokine production in CD94/NKG2C(+) T cell clones, inducing as well IL-2Ralpha expression and a proliferative response [25].
• Expression of HLA-G inhibits NK cells expressing the CD94/NKG2 class of receptors, though an interaction with these receptors has not been directly demonstrated [26].
• Similar to NK cells, most CD8 T cells that express high levels of CD94 co-express NKG2A, the inhibitory isoform [27].
• CD160 is an Ig-like activating NK cell receptor expressed on the majority of circulating NK cells [28].

Other interactions of KLRD1

• Surface expression of HLA-E was enough to protect target cells from lysis by CD94/NKG2A+ NK-cell clones [7].
• In the absence of lymphocyte-stimulating cytokines or when contact with AFT024 was prohibited, NK cell progeny were killer immunoglobulinlike receptor (KIR) and CD94 lectin receptor negative [29].
• Purified CD56(+) populations stimulated with HCMV-infected cells did not proliferate, but the expansion of the CD94/NKG2C(+) subset was detected in the presence of interleukin-15 (IL-15) [16].
• The CD94/NKG2C killer lectin-like receptor constitutes an alternative activation pathway for a subset of CD8+ T cells [25].
• However, a conserved 24-amino acid sequence, present in all members of the NKG2 family, suggests that NKG2-F is also able to form heterodimers with CD94 [30].

Analytical, diagnostic and therapeutic context of KLRD1

• By contrast, NK clones bearing the homologous CD94/p39 receptor are triggered upon its ligation by CD94-specific mAbs [31].
• The immunoprecipitation of CD94 heterodimer showed a 39-kDa band with a similar m.w. to the activatory heterodimer found on some NK clones [32].
• Thus, triggering NK cell receptor monitoring on macaque NK cells is possible and could provide a valuable tool for assessing NK cell function during experimental infections and for exploring possible differences in immune correlates of protection in humans compared with cynomolgus and rhesus macaques undergoing different vaccination strategies [33].
• Analysis of the expression of the various HLA class I-specific inhibitory NK receptors revealed the presence of high proportions of CD94/ NKG2-A+ cells, while the NK receptors belonging to the Ig superfamily were undetectable both by immunofluorescence and by RT-PCR analysis [34].
• Furthermore, their ability to bind solubilized immunoaffinity-purified HLA class I antigens, either alone or following association with CD94 lectin domains, was evaluated using flow cytometry and Western blot analyses [35].

References