Cloning of Immunoglobulin-Superfamily Members Associated with HLA-C and HLA-B Recognition by Human Natural Killer Cells

Colonna, Marco; Samaridis, Jacqueline

doi:10.1126/science.7716543

Cited by 687 publications

(428 citation statements)

References 29 publications

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“…Inhibitory NK-cell receptors specific for classical MHC class I molecules belong to the mouse Ly49 (also known as KLRA) receptor family 6,7 and the human killer immunoglobulin-like receptor (KIR) family [8][9][10] . The molecular cloning of NK-cell receptors led to the identification of additional MHC class I receptors, which had not been predicted on the basis of functional experiments: human leukocyte immunoglobulin-like receptors (LILRs; also known as LIRs, ILTs or MIRs), and their orthologues, mouse paired immunoglobulin-like receptors (PIRs), as well as the heterodimeric CD94-NKG2 (NK group 2) receptors 11-14 (TABLE 1).…”

Section: 'Missing-self' Hypothesismentioning

confidence: 99%

Cis interactions of immunoreceptors with MHC and non-MHC ligands

2008

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The conventional wisdom is that cell-surface receptors interact with ligands expressed on other cells to mediate cell-to-cell communication (trans interactions). Unexpectedly, it has recently been found that two classes of receptors specific for MHC class I molecules not only interact with MHC class I molecules expressed on opposing cells, but also with those on the same cell. These cis interactions are a feature of immunoreceptors that inhibit, rather than activate, cellular functions. Here, we review situations in which cis interactions have been observed, the characteristics of receptors that bind in trans and cis, and the biological roles of cis recognition.As their name indicates, MHC molecules were discovered and characterized based on their role in inducing potent rejection of tissue grafts. However, the physiological role of MHC molecules remained enigmatic until ground-breaking studies demonstrated the fundamental importance of the MHC complex in T-cell-mediated immunity to infection 1 . A vast amount of subsequent work elucidated how T-cell receptors (TCRs) recognize self MHC molecules in complex with non-self peptides derived from microbial or other foreign proteins.Transplantation biology provided early evidence for the existence of an alternative immunerecognition strategy. The laws of transplantation predicted that tissue grafts were accepted as long they displayed a subset of the recipient's MHC alleles 2 . Indeed, MHC heterozygous offspring from two mouse strains that differed at the MHC locus (F1 hybrids) accepted solid tissue grafts from either parent. However, parental bone-marrow grafts were rejected by irradiated F1 hybrid mice, a phenomenon termed hybrid resistance 3 . This observation suggested a novel type of immune recognition, which was controlled by MHC genes. The basis for this phenomenon remained obscure until several lines of research converged on the proposal that the lack of (appropriate) MHC class I molecules on host cells resulted in natural killer (NK)-cell-mediated rejection (the 'missing-self' hypothesis) 4 . Subsequent work showed that NK cells expressed MHC-class-I-specific inhibitory receptors, which protected normal host cells from NK-cell-mediated attack. Consequently, the loss of MHC class I molecules, which arises owing to infection or transformation, and is likely selected for by cytolytic T cells, renders host cells susceptible to NK-cell-mediated lysis, as inhibitory receptors are no longer engaged. These studies led to the identification of families of MHC class I receptors expressed by NK cells. Hybrid resistance was eventually explained by the selectivity of inhibitory receptors for certain MHC class I alleles together with the differential expression of these receptors by subsets of NK cells. As a consequence, a subset of NK cells in MHC heterozygous e-mails: Werner.Held@licr.unil.ch; mariuzza@carb.nist.gov. NIH Public Access MHC recognition in trans and cis T-cell receptorsX-ray crystallographic studies of TCRs bound to peptide-MHC-class-I or peptide-M...

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Section: 'Missing-self' Hypothesismentioning

confidence: 99%

Cis interactions of immunoreceptors with MHC and non-MHC ligands

2008

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“…In the mouse, the CD94/ NKG2A heterodimer interacts with the class Ib molecule Qa-1 b in complex with leader peptides from some class Ia allotypes such as H-2D b [11,12]. Members of the human killer cell immunoglobulin receptor (KIR) family bind to different allotypes of HLA class Ia [13][14][15]. The corresponding function in mice is mediated by Ly49 receptors, which belong to a family of dimeric type II integral membrane proteins with a C-type (calcium-dependent) lectin-like domain [16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

In vivo tumor cell rejection induced by NK cell inhibitory receptor blockade: Maintained tolerance to normal cells even in the presence of IL‐2

et al. 2010

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Missing-self-reactivity can be mimicked by blocking self-specific inhibitory receptors on NK cells, leading to increased rejection of syngeneic tumor cells. Using a mouse model, we investigated whether Ab-mediated blocking of inhibitory receptors, to a degree where NK cells rejected syngeneic tumor cells, would still allow self-tolerance toward normal syngeneic cells. Ly49C/I inhibitory receptors on C57BL/6 (H-2 b ) NK cells were blocked with F(ab') 2 fragments of the mAb 5E6. Inhibitory receptor blockade in vivo caused rejection of i.v. inoculated fluorescence-labeled syngeneic lymphoma line cells but not of syngeneic spleen cells, BM cells or lymphoblasts. The selective rejection of tumor cells was NK celldependent and specifically induced by Ly49C/I blockade. Moreover, selective tumor rejection was maintained after treatment with 5E6 F(ab') 2 for 9 wk, arguing against the induction of NK cell anergy or autoreactivity during this time. Combination therapy using 5E6 F(ab') 2 together with high dose IL-2 treatment further increased lymphoma cell rejection. In addition, combination therapy reduced growth of melanoma cell line tumors established by s.c. inoculation 3 days before start of treatment. Our results demonstrate that inhibitory receptor blockade does not result in attack on normal cells, despite potent reactivity against MHC class I-expressing tumors.

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“…1,2 This is an extremely variable and rapidly evolving region of the mammals genome that encodes a family of receptors expressed on the surface of NK-and T-lymphocyte subpopulations. [3][4][5][6] Some KIR inhibit lymphocyte function upon recognition of HLA class I molecules on potential target cells. By means of these KIR, NK cells survey the normal function of the endogenous antigen presentation pathway, and eliminate infected and tumour cells in which HLA expression is subverted.…”

Section: Introductionmentioning

confidence: 99%

Duplication, mutation and recombination of the human orphan gene KIR2DS3 contribute to the diversity of KIR haplotypes

et al. 2008

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The KIR2DS3 gene is an activating homologue of the inhibitory killer-cell immunoglobulin-like receptors (KIR) that recognize HLA-C molecules, enabling NK cells to survey the normal function of endogenous antigen presentation. The genetics of KIR2DS3 is complicated by the existence of alleles with similar coding sequences that map to different regions of the KIR complex in chromosome 19, or whose location in this complex is unknown. Here, by studying the family segregation of the KIR alleles 2DS3*001, *002 and *003N, and the distribution of these in unrelated individuals, we demonstrate the existence of two paralogous KIR2DS3 genes that can be inherited separately or, as it happens frequently in Caucasoids due to linkage disequilibrium, together. Each KIR2DS3 gene is almost invariably associated in its 5 0 end to a different copy of KIR2DL5, a gene previously shown to be duplicated in humans. KIR2DL5 and KIR2DS3 thus form two highly homologous gene clusters situated in the centromeric and the telomeric intervals of KIR haplotypes. Recombination between those clusters is the likely origin of new haplotypes, characterized in this study, which harbour further duplications or deletions of multiple KIR genes. Our results help understand the genetics of KIR2DS3 and the diversity of human KIR genotypes.

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Cloning of Immunoglobulin-Superfamily Members Associated with HLA-C and HLA-B Recognition by Human Natural Killer Cells

Cited by 687 publications

References 29 publications

Cis interactions of immunoreceptors with MHC and non-MHC ligands

Cis interactions of immunoreceptors with MHC and non-MHC ligands

In vivo tumor cell rejection induced by NK cell inhibitory receptor blockade: Maintained tolerance to normal cells even in the presence of IL‐2

Duplication, mutation and recombination of the human orphan gene KIR2DS3 contribute to the diversity of KIR haplotypes

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